[go: up one dir, main page]

EP3365340B1 - Composés hétérocycliques utilisés comme immunomodulateurs - Google Patents

Composés hétérocycliques utilisés comme immunomodulateurs Download PDF

Info

Publication number
EP3365340B1
EP3365340B1 EP16787687.9A EP16787687A EP3365340B1 EP 3365340 B1 EP3365340 B1 EP 3365340B1 EP 16787687 A EP16787687 A EP 16787687A EP 3365340 B1 EP3365340 B1 EP 3365340B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cancer
cycloalkyl
compound
membered heterocycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP16787687.9A
Other languages
German (de)
English (en)
Other versions
EP3365340A1 (fr
Inventor
Liangxing Wu
Bo Shen
Jingwei Li
Zhenwu Li
Kai Liu
Fenglei Zhang
Wenqing Yao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Incyte Corp
Original Assignee
Incyte Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Incyte Corp filed Critical Incyte Corp
Publication of EP3365340A1 publication Critical patent/EP3365340A1/fr
Application granted granted Critical
Publication of EP3365340B1 publication Critical patent/EP3365340B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application is concerned with pharmaceutically active compounds.
  • the disclosure provides compounds as well as their compositions and methods of use.
  • the compounds modulate PD-1/PD-L1 protein/protein interaction and are useful in the treatment of various diseases including infectious diseases and cancer.
  • the immune system plays an important role in controlling and eradicating diseases such as cancer.
  • cancer cells often develop strategies to evade or to suppress the immune system in order to favor their growth.
  • One such mechanism is altering the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells ( Postow et al, J. Clinical Oncology 2015, 1-9 ).
  • Blocking the signaling of an inhibitory immune checkpoint, such as PD-1, has proven to be a promising and effective treatment modality.
  • PD-1 Programmed cell death-1
  • CD279 is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages ( Greenwald et al, Annu. Rev. Immunol 2005, 23:515-548 ; Okazaki and Honjo, Trends Immunol 2006, (4):195-201 ). It functions as an intrinsic negative feedback system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance.
  • PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection ( Sharpe et al, Nat Immunol 2007 8, 239-245 ; Postow et al, J. Clinical Oncol 2015, 1-9 ).
  • the structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain ( Parry et al, Mol Cell Biol 2005, 9543-9553 ).
  • the intracellular domain contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T cell receptor-mediated signals.
  • PD-1 has two ligands, PD-L1 and PD-L2 ( Parry et al, Mol Cell Biol 2005, 9543-9553 ; Latchman et al, Nat Immunol 2001, 2, 261-268 ), and they differ in their expression patterns.
  • PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and the expression is further increased after IFN- ⁇ treatment ( Iwai et al, PNAS2002, 99(19): 12293-7 ; Blank et al, Cancer Res 2004, 64(3):1140-5 ).
  • tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types ( Wang et al, Eur J Surg Oncol 2015 ; Huang et al, Oncol Rep 2015 ; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464 ).
  • PD-L2 expression in contrast, is more restricted and is expressed mainly by dendritic cells ( Nakae et al, J Immunol 2006, 177:566-73 ).
  • Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal that inhibits IL-2 and IFN- ⁇ production, as well as cell proliferation induced upon T cell receptor activation ( Carter et al, Eur J Immunol 2002, 32(3):634-43 ; Freeman et al, J Exp Med 2000, 192(7):1027-34 ).
  • the mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling such as Syk and Lck phosphorylation ( Sharpe et al, Nat Immunol 2007, 8, 239-245 ).
  • Activation of the PD-1 signaling axis also attenuates PKC- ⁇ activation loop phosphorylation, which is necessary for the activation of NF- ⁇ B and AP1 pathways, and for cytokine production such as IL-2, IFN- ⁇ and TNF ( Sharpe et al, Nat Immunol 2007, 8, 239-245 ; Carter et al, Eur J Immunol 2002, 32(3):634-43 ; Freeman et al, J Exp Med 2000, 192(7):1027-34 ).
  • PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy ( Nishimura et al, Immunity 1999, 11:141-151 ; Nishimura et al, Science 2001, 291:319-322 ).
  • LCMV model of chronic infection it has been shown that PD-1/PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus-specific CD8 T cells ( Barber et al, Nature 2006, 439, 682-7 ).
  • the present disclosure provides, inter alia , a compound of Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein constituent variables are defined herein and in the claims.
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the present disclosure further provides compounds, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in methods of modulating or inhibiting PD-1/PD-L1 protein/protein interaction, wherein the disease or disorder is a viral infection or cancer.
  • the present disclosure further provides compounds, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in methods of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of said compound of the disclosure, or pharmaceutically acceptable salt or stereoisomer thereof.
  • the present disclosure provides, inter alia , a compound of Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • two adjacent R 7 substituents on the phenyl ring taken together with the carbon atoms to which they are attached, form a fused phenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 5-6 cycloalkyl ring, wherein the fused 5- or 6-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R q substituents.
  • the compounds, or pharmaceutically acceptable salts or stereoisomers thereof, as described herein are useful as inhibitors of the PD-1/PD-L1 protein/protein interaction.
  • compounds or pharmaceutically acceptable salts or stereoisomers thereof as described herein can disrupt the PD-1/PD-L1 protein/protein interaction in the PD-1 pathway.
  • the present disclosure provides compounds having Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 4 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O
  • the present disclosure provides compounds having Formula (III): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (III) are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • the present disclosure provides compounds having Formula (IV): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (IV) are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • the present disclosure provides compounds having Formula (V): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (V) are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • the present disclosure provides compounds having Formula (VI): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (VI) are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • R 1 , R 2 , R 3 and R 5 are each H.
  • the moiety: is selected from: , wherein the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Formula (II) above or any embodiment of compounds of Formula (II) as described herein.
  • X 1 is N
  • X 2 is CH
  • X 3 , X 5 and X 6 are each CH
  • Y 1 is N
  • Y 2 is C.
  • X 1 is CH
  • X 2 is CH
  • X 3 , X 5 and X 6 are each CH
  • Y 1 is C
  • Y 2 is N.
  • X 1 is CH
  • X 2 is CH
  • X 3 and X 6 are each CH
  • X 5 is N
  • Y 1 is C
  • Y 2 is N.
  • X 1 is N
  • X 2 is CH
  • X 3 and X 6 are each N
  • X 5 is CH
  • Y 1 is N
  • Y 2 is C.
  • X 1 is N
  • X 2 is CH
  • X 3 and X 5 are each CH
  • X 6 is N
  • Y 1 is N
  • Y 2 is C.
  • X 1 is N
  • X 2 is CH
  • X 3 and X 6 are each CH
  • X 5 is N
  • Y 1 is N
  • Y 2 is C.
  • X 1 is N
  • X 2 is CH
  • X 5 and X 6 are each CH
  • X 3 is N
  • Y 1 is N and Y 2 is C.
  • X 1 and X 2 are each N, X 3 , X 5 and X 6 are each CH, Y 1 is C and Y 2 is N.
  • X 1 and X 2 are each N, X 3 is CH, X 5 is N, X 6 is CR 6 , Y 1 is C and Y 2 is N.
  • X 1 is N
  • X 2 is CH
  • X 3 and X 5 are each CH
  • X 6 is CR 6
  • Y 1 is N and Y 2 is C.
  • X 1 and X 2 are each N, X 3 and X 5 are each CH, X 6 is CR 6 , Y 1 is N and Y 2 is C.
  • R 9 is C 1-4 alkyl or CN.
  • R 9 is CH 3 or CN.
  • R 7 and R 8 are each H.
  • R 8 is H.
  • X 2 , X 3 , X 5 and X 6 are each CH.
  • X 1 , X 2 , X 3 , X 5 and X 6 are each CH.
  • X 1 , X 2 , X 3 and X 6 are each CH.
  • X 2 and X 5 are each CH.
  • X 2 , X 3 and X 5 are each CH.
  • X 2 and X 6 are each CH.
  • X 2 , X 5 and X 6 are each CH.
  • X 3 , X 5 and X 6 are each CH.
  • X 3 is CH.
  • R 4 is C 1-4 alkyl substituted with R b .
  • R b is NHR c or NR c R c .
  • R b is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl.
  • R 4 is C 1-4 alkyl substituted with R d .
  • R 4 is C 1-4 alkyl substituted with R f . In other embodiments, R 4 is C 1-4 alkyl substituted with R h . In other embodiments, R 4 is C 1-4 alkyl substituted with R j . In other embodiments, R 4 is C 1-4 alkyl substituted with R n . In other embodiments, R 4 is C 1-4 alkyl substituted with R q .
  • R 4 is -CH 2 R b .
  • R b is NHR c or NR c R c .
  • R b is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl.
  • R 4 is -CH 2 -R d .
  • R 4 is - CH 2 -R f .
  • R 4 is -CH 2 -R h . In other embodiments, R 4 is -CH 2 -R j . In other embodiments, R 4 is -CH 2 -R n . In other embodiments, R 4 is -CH 2 -R q .
  • R 4 is 2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or 2-carboxypiperidin-1-ylmethyl.
  • R 6 is H, halo or C 1-6 alkyl optionally substituted with 1-3 R q substituents.
  • R 6 is H, halo or CH 3 .
  • C 1-6 alkyl is specifically intended to individually disclose (without limitation) methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • n-membered typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -NR(CR'R") n - includes both -NR(CR'R") n - and -(CR'R") n NR- and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or "aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • optionally substituted means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 and the like.
  • alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched.
  • C n-m alkyl refers to an alkyl group having n to m carbon atoms.
  • An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n -propyl, isopropyl, n -butyl, tert -butyl, isobutyl, sec -butyl; higher homologs such as 2-methyl-1-butyl, n -pentyl, 3-pentyl, n -hexyl, 1,2,2-trimethylpropyl and the like.
  • alkenyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • C n-m alkenyl refers to an alkenyl group having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n -propenyl, isopropenyl, n-butenyl, sec -butenyl and the like.
  • alkynyl employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds.
  • An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • C n-m alkynyl refers to an alkynyl group having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • C n-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.
  • alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above.
  • C n-m alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n -propoxy and isopropoxy), t -butoxy and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • amino refers to a group of formula -NH 2 .
  • carboxylate refers to a group of formula -C(O)NH 2 .
  • halo refers to fluoro, chloro, bromo and iodo.
  • halo refers to a halogen atom selected from F, Cl, or Br.
  • halo groups are F.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • C n-m haloalkyl refers to a C n-m alkyl group having n to m carbon atoms and from at least one up to ⁇ 2(n to m)+1 ⁇ halogen atoms, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 and the like.
  • the haloalkyl group is a fluoroalkyl group.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above.
  • C n-m haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons.
  • Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N -oxide group.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e. , having (4n + 2) delocalized ⁇ (pi) electrons where n is an integer).
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings).
  • C n-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.
  • heteroaryl or “heteroaromatic,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring.
  • Example heteroaryl groups include, but are not limited to, pyridintl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2- b ]thiazolyl, purinyl, and the like.
  • pyridintl pyridyl
  • pyrimidinyl pyrazinyl
  • pyridazinyl
  • a five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more ( e.g ., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more ( e.g ., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • C n-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C 3-7 ).
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C 3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused ( i.e. , having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) ring systems.
  • the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage ( e.g ., C(O), S(O), C(S) or S(O) 2 , N -oxide etc. ) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused ( i.e. , having a bond in common with) to the heterocycloalkyl ring, e.g ., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, and thiomorpholino.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc .). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention have the ( R )-configuration. In other embodiments, the compounds have the ( S )-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or ( S ), unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 H- and 3 H -imidazole, 1 H-, 2 H- and 4 H- 1,2,4-triazole, 1 H - and 2 H - isoindole and 1 H - and 2 H -pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • solvents e.g., hydrates and solvates
  • the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, e.g., a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g ., a temperature from about 20 °C to about 30 °C.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418 , Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups is described, e.g ., in Kocienski, Protecting Groups, (Thieme, 2007 ); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000 ); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007 ); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297 ; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006 ).
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e . g ., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e . g ., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the compounds of Formula 4 can be prepared according to Scheme 1 .
  • the N-bridged heteroaryl compounds of Formula 10 can also be prepared according to Scheme 2 .
  • substituted phenyl boronic esters 6 under standard Suzuki coupling condition (e.g., in the presence of a palladium catalyst and a suitable base) to produce the biphenyl compounds 7 .
  • Bromination of the methyl ketones 7 using brominating reagents including, but not limited, to copper(II) bromide can generate ⁇ -bromo ketones 8 .
  • Condensation of ⁇ -bromo ketones 8 and amino heterocycles 9 in polar solvents (e.g., isopropanol) under heating can afford the N-bridged heteroaryl compounds 10 .
  • the triazole-containing heteroaryl halides of formula 13 (Hal 4 is a halide such as Br or I) can be formed according to Scheme 3 . Coupling of amino heterocycles 9 with ethoxycarbonyl isothiocyanate 11 , followed by treatment with hydroxylamine hydrochloride and diisopropylethylamine (DIPEA) can form N-bridged heteroaryl amines 12 . Conversion of the primary amine in 12 to halides can be achieved under Sandmeyer reaction conditions [i.e. in the presence of tert-butyl nitrite and a halogen sources such as CuBr 2 or I 2 ] to generate the N-bridged heteraryl halides 13 .
  • DIPEA diisopropylethylamine
  • the N-bridged heteroaryl compounds of Formula 18 can be prepared according to Scheme 4 , starting from compounds of formula 14 or 15 which can be prepared according to procedures as described in Scheme 1 or 2 .
  • Heteroaryl esters 14 can be reduced to aldehydes 16 via a sequence of reduction (e.g., LiAlH 4 or LiBH 4 as reducing reagents) and oxidation (e.g., Dess-Martin periodinane as oxidant).
  • the aldehydes 16 might also be formed via direct reduction of esters 14 under mild reducing conditions [e.g., using diisobutylaluminium hydride (DIBAL) as the reducing agent at low temperature].
  • DIBAL diisobutylaluminium hydride
  • aldehydes 16 can be formed through a direct reduction of nitriles 15 with DIBAL as the reducing reagent at low temperature. Then the aldehydes 16 can react with amines 17 of formula HNR c R c under standard reductive amination conditions (e.g., sodium triacetoxyborohydride or sodium cyanoborohydride as reducing reagents) to generate compounds of formula 18 .
  • standard reductive amination conditions e.g., sodium triacetoxyborohydride or sodium cyanoborohydride as reducing reagents
  • the halide in compounds 19 can be converted to vinyl group to give olefins 20 , under standard Suzuki coupling condition (e.g., with vinylboronic acid pinaco ester in the presence of a palladium catalyst and a suitable base).
  • the vinyl group in compounds 20 can be oxidatively cleaved by NaIO 4 in the presence of catalytic amount of OsO 4 to form aldehydes 16 .
  • Compounds of Formula 25 can be prepared using procedures as outlined in Scheme 6 .
  • a palladium catalyst such as, tetrakis(triphenylphosphine) palladium(O), palladium(II) acetate.
  • M is a boronic acid, boronic ester or an appropriately substituted metal
  • Suzuki coupling conditions e.g., in the presence of a palladium catalyst and a suitable base
  • Stille coupling conditions e.g., in the presence of a palladium catalyst
  • Negishi coupling conditions e.g
  • compound 24 can be a cyclic amine (where M is H and attached to an amine nitrogen in ring Cy) and the coupling of aryl halide 23 with the cyclic amine 24 can be performed under Buchwald amination conditions (e.g., in the presence of a palladium catalyst and a base such as sodium tert-butoxide).
  • Buchwald amination conditions e.g., in the presence of a palladium catalyst and a base such as sodium tert-butoxide.
  • Compounds of Formula 25 can be prepared using the procedures as outlined in Scheme 7 .
  • Selective coupling of aryl halides 26 with compounds of formula 24 [M is a boronic acid, boronic ester or an appropriately substituted metal, e.g., M is B(OR) 2 , Sn(Alkyl) 4 , or Zn-Hal] can be achieved under suitable Suzuki coupling, Stille coupling or Negishi coupling conditions to give compounds of Formula 27 .
  • compound 24 is a cyclic amine (e.g., M is H and attached to nitrogen in ring Cy)
  • the coupling can be achieved under Buchwald amination conditions.
  • Conversion of compound 27 to the final product 25 can be achieved using similar conditions as described in Scheme 1 .
  • Compounds of the present disclosure can inhibit the activity of PD-1/PD-L1 protein/protein interaction and, thus, are useful in treating diseases and disorders associated with activity of PD-1 and the diseases and disorders associated with PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80).
  • the compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof are useful for therapeutic administration to enhance immunity in cancer or chronic infection, including enhancement of response to vaccination.
  • the present disclosure provides a compound for use in a method for inhibiting the PD-1/PD-L1 protein/protein interaction.
  • the method includes administering to an individual or a patient a compound of Formula (II) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancer or infection diseases.
  • any of the compounds of the disclosure including any of the embodiments thereof, may be used.
  • the compounds of the present disclosure inhibit the PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway blockade.
  • the blockade of PD-1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans.
  • the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula (II) or a salt or stereoisomer thereof such that growth of cancerous tumors is inhibited.
  • a compound of Formula (II) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors.
  • a compound of Formula (II) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof can be used in conjunction with other agents or standard cancer treatments, as described below.
  • the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (II) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or of a salt or stereoisomer thereof.
  • the present disclosure provides a method for inhibiting growth of tumor cells in an individual or a patient.
  • the method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (II) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a salt or a stereoisomer thereof.
  • a method for treating cancer includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • cancers include those whose growth may be inhibited using compounds of the disclosure and cancers typically responsive to immunotherapy.
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leuk
  • cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • melanoma e.g., metastatic malignant melanoma
  • renal cancer e.g. clear cell carcinoma
  • prostate cancer e.g. hormone refractory prostate adenocarcinoma
  • breast cancer e.g. hormone refractory prostate adenocarcinoma
  • colon cancer e.g. non-small cell lung cancer
  • lung cancer e.g. non-small cell lung cancer
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e . g ., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myelom
  • solid tumors
  • PD-1 pathway blockade with compounds of the present disclosure can also be used for treating infections such as viral, bacteria, fungus and parasite infections.
  • the present disclosure provides a method for treating infections such as viral infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, a salt thereof.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limit to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, and measles virus.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., adenovirus
  • influenza virus flaviviruses
  • the present disclosure provides a method for treating bacterial infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic bacteria causing infections treatable by methods of the disclosure include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • the present disclosure provides a method for treating fungus infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic fungi causing infections treatable by methods of the disclosure include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis, etc.
  • Cryptococcus neoformans Aspergillus (fumigatus, niger, etc.)
  • Genus Mucorales micor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Paracoccidioides brasiliensis Coccidio
  • the present disclosure provides a method for treating parasite infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
  • mice preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to one or more of (1) inhibiting the disease; e . g ., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder ( i.e ., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e . g ., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder ( i.e ., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e . g ., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • Cancer cell growth and survival can be impacted by multiple signaling pathways.
  • Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.
  • the compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of diseases, such as cancer or infections.
  • diseases such as cancer or infections.
  • cancers include solid tumors and liquid tumors, such as blood cancers.
  • infections include viral infections, bacterial infections, fungus infections or parasite infections.
  • the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF- ⁇ R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF ⁇ R, PDGF ⁇ R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,
  • the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections.
  • inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor such as PI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, a CSFIR inhibitor, a TAM
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is anti-PDl antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
  • the anti-PDl antibody is pembrolizumab.
  • the anti PD-1 antibody is SHR-1210.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody.
  • the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or MK-4166.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • OX40 e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562.
  • the OX40L fusion protein is MEDI6383.
  • the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
  • an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.
  • the proteasome inhibitor is carfilzomib.
  • the corticosteroid is dexamethasone (DEX).
  • the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
  • the compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumortargeted therapy, adjuvant therapy, immunotherapy or surgery.
  • immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor and the like.
  • the compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics.
  • Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazox
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • Examples of antibodies to PD-1 and/or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
  • the compounds of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
  • the compounds of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
  • tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • HPV Human Papilloma Viruses
  • HBV and HCV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself.
  • the compounds of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.
  • the compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells.
  • the compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.
  • the compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.
  • the compounds of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.
  • Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • human papillomavirus influenza, hepatitis A,
  • Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis, etc.
  • Cryptococcus neoformans Aspergillus (fumigatus, niger, etc.)
  • Genus Mucorales micor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Paracoccidioides brasiliensis C
  • Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
  • more than one pharmaceutical agent When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).
  • the compounds of the present disclosure can be administered in the form of pharmaceutical compositions.
  • a composition comprising a compound of Formula (II) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated.
  • Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container.
  • a carrier in the form of, e.g., a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art see, e.g., WO 2002/000196 .
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • SMCC silicified microcrystalline cellulose
  • the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.
  • the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide.
  • the composition further comprises magnesium stearate or silicon dioxide.
  • the microcrystalline cellulose is Avicel PH102 TM .
  • the lactose monohydrate is Fast-flo 316 TM .
  • the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier TM ) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV TM ).
  • the polyethylene oxide is polyethylene oxide WSR 1105 ( e.g., Polyox WSR 1105 TM ).
  • a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade).
  • the composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the applicable regulations of the U.S. Food and Drug Administration.
  • suitable formulations may be sterile and/or substantially isotonic and/or in full compliance with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.
  • the active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • the therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, e.g ., about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g., glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the compound of the invention.
  • the topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues.
  • another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc. ) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including human, and for identifying PD-L1 ligands by inhibition binding of a labeled compound.
  • the present invention includes PD-1/PD-L1 binding assays that contain such labeled compounds.
  • the present invention further includes isotopically-substituted compounds of the disclosure.
  • An “isotopically-substituted” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature ( i.e., naturally occurring). It is to be understood that a "radio-labeled” compound is a compound that has incorporated at least one isotope that is radioactive (e.g., radionuclide).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PD-L1 protein labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I, 131 I, 35 S or will generally be most useful.
  • radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.
  • a labeled compound of the invention can be used in a screening assay to identify and/or evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled can be evaluated for its ability to bind a PD-L1 protein by monitoring its concentration variation when contacting with the PD-L1 protein, through tracking of the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PD-L1 protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PD-L1 protein directly correlates to its binding affinity.
  • the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • kits useful useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (II), or any of the embodiments thereof.
  • kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components can also be included in the kit.
  • Step 4 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane
  • Example 1 To a solution of the crude product from Step 4 in 1,4-dioxane (1 mL) and water (0.2 mL) were added 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane (Example 1, Step 4: 57 mg, 0.20 mmol), potassium phosphate (69 mg, 0.32 mmol) and dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (10 mg, 0.01 mmol). The resulting mixture was purged with N 2 then stirred at 90 °C for 4 h.
  • Step 2 methyl (2S)-1- ⁇ [2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl]piperidine-2-carboxylate
  • Example 1 To the mixture of the crude product from Step 2 in 1,4-dioxane (0.3 mL) and water (0.07 mL) was added 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane (Example 1, Step 4: 21 mg, 0.070 mmol), potassium phosphate (20. mg, 0.092 mmol) and dichloro[1,1'-bis(dicyclohexylphosphino) ferrocene]palladium(II) (3 mg, 0.004 mmol). The mixture was purged with N 2 , then heated at 90 °C for 4 h.
  • Step 5 6-(2-methylbiphenyl-3-yl)-2-vinylimidazo[1,2-b][1,2,4]triazine
  • Step 6 6-(2-methylbiphenyl-3-yl)imidazo ⁇ 1,2-b ⁇ 1,2,4 ⁇ triazine-2-carbaldehyde
  • Step 7 2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)ethanol
  • Step 1 6-bromo-8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
  • Step 2 8-methyl-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
  • Step 4 2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol
  • Step 2 6-bromo-8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine
  • Step 3 8-chloro-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine
  • Step 4 8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbaldehyde
  • Step 5 2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol
  • Step 2 6-(1,3-dioxolan-2-yl)-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine
  • Step 1 methyl 2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate
  • Step 4 (2S)-1- ⁇ [2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl)piperidine-2-carboxylic acid
  • Ethoxycarbonyl isothiocyanate (606 ⁇ L, 5.36 mmol) was added to a solution of (2-aminopyridin-4-yl)methanol ( Aldrich, cat # 714577: 555 mg, 4.47 mmol) in 1,4-dioxane (22.4 mL). The reaction mixture was stirred at room temperature for 15 h. The mixture was concentrated and the residue was dissolved in methanol (16.0 mL)/ethanol (16.0 mL), then N , N -diisopropylethylamine (1.56 mL, 8.94 mmol) was added, followed by hydroxylamine hydrochoride (932 mg, 13.4 mmol).
  • Step 5 2-( ⁇ [2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl ⁇ amino)ethanol
  • Step 1 methyl 2-amino[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
  • Step 2 methyl 2-bromo[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
  • Step 3 methyl 2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
  • Diisobutylaluminum hydride in DCM (643 ⁇ L, 0.643 mmol) was added to the solution of methyl 2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (184 mg, 0.536 mmol) in Et 2 O (5 mL) at 0 °C.
  • the mixture was stirred at room temperature for 3 h then another portion of diisobutylaluminum hydride (1M in DCM, 1 mL, 1 mmol) was added.
  • the mixture was stirred at room temperature for another 2 h then quenched with aqueous NH 4 Cl and stirred with Rochelle salt, and then extracted with DCM.
  • Step 6 2-([[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl ⁇ amino)ethanol
  • Ethanolamine (8.7 ⁇ L, 0.15 mmol) was added to a solution of 2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (9.0 mg, 0.029 mmol) in N,N- dimethylformamide (0.28 mL), followed by acetic acid (2.5 ⁇ L, 0.04 mmol).
  • the reaction mixture was stirred at room temperature for 10 min then sodium cyanoborohydride (5.4 mg, 0.087 mmol) was added.
  • Step 3 5-methyl-2-(2-methylbiphenyl-3-yl)-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine
  • Step 5 2-( ⁇ [5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4 ⁇ triazolo ⁇ 1,5-c]pyrimidin-7-yl]methyl ⁇ amino)ethanol
  • Ethanolamine (5.9 ⁇ L, 0.097 mmol) was added to the solution of 5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidine-7-carbaldehyde (6.4 mg, 0.019 mmol) in N,N -dimethylformamide (0.19 mL), followed by acetic acid (1.7 ⁇ L, 0.029 mmol). The mixture was stirred at room temperature for 10 min then sodium cyanoborohydride (3.7 mg, 0.059 mmol) was added.
  • Step 1 ethyl ( ⁇ [3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino]carbonothioyl)carbamate
  • tert -Butyl nitrite (579 ⁇ L, 4.87 mmol) was added to a suspension of (2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (403 mg, 2.03 mmol) and copper(II) bromide (906 mg, 4.06 mmol) in acetonitrile (19.6 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried, filtered and concentrated.
  • Step 5 8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde
  • Dess-Martin periodinane (706 mg, 1.66 mmol) was added to a solution of [8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol (291 mg, 0.832 mmol) in dichloromethane (3.94 mL). The mixture was stirred at room temperature for 1 h. The mixture was quenched with aq. sodium bisulfite and extracted with dichloromethane. The organic phase was dried over a drying agent and filtered. The filtrate was concentrated.
  • Step 6 2-( ⁇ [8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl ⁇ amino)ethanol
  • Ethanolamine (186 ⁇ L, 3.09 mmol) was added to a solution of 8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (215 mg, 0.618 mmol) in N,N- dimethylformamide (3.87 mL), followed by trifluoroacetic acid (143 ⁇ L).
  • the reaction mixture was stirred at room temperature for 10 min.
  • sodium cyanoborohydride (116 mg, 1.85 mmol) was added.
  • the reaction mixture was stirred at room temperature overnight.
  • the crude was diluted with water and extracted with dichloromethane. The organic phase was concentrated.
  • Step 2 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
  • Step 3 2-(8-chloro-6- ⁇ [(2-hydroxyethyl)amino]methyl][1,2,4 ⁇ triazolo ⁇ 1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
  • Example A PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) binding assay
  • the assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 ⁇ L. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assays were carried out at 25° C in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a Histag at the C-terminus was purchased from AcroBiosystems (PD1-H5229).
  • Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257).
  • PD-L1 and PD-1 proteins were diluted in the assay buffer and 10 ⁇ L was added to the plate well. Plates were centrifuged and proteins were preincubated with inhibitors for 40 minutes. The incubation was followed by the addition of 10 ⁇ L of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLight ® -Allophycocyanin (APC, PerkinElmer-AD0059H).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (27)

  1. Composé de formule (II) :
    Figure imgb0126
     ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant,
    l'un de Y1 et Y2 étant N et l'autre de Y1 et Y2 étant C ;
    X1 étant N ou CR1 ;
    X2 étant N ou CR2 ;
    X3 étant N ou CR3 ;
    X5 étant N ou CR5 ;
    X6 étant N ou CR6 ;
    R1, R2 et R8 étant chacun H ;
    R9 étant C1-4 alkyle ou CN ;
    R3 et R5 étant chacun H ;
    R6 et R7 étant chacun indépendamment choisis parmi H, halogéno, C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C1-6-halogénoalkyle, C1-6-halogénoalcoxy, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 14 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 14 chaînons)-C1-4-alkyle-, (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra et S(O)2NRaRa, les C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 14 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 14 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de R6 et R7 étant chacun éventuellement substitués par 1, 2, 3 ou 4 substituants Rb ;
    R4 étant halogéno, C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C1-6-halogénoalkyle, C1-6-halogénoalcoxy, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 14 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 14 chaînons)-C1-4-alkyle-, (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra et S(O)2NRaRa, les C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 14 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 14 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de R4 étant chacun éventuellement substitués par 1, 2, 3 ou 4 substituants Rb ;
    ou deux substituants R7 adjacents sur le cycle phényle, pris ensemble avec les atomes de carbone auxquels ils sont fixés, formant un cycle phényle condensé, un cycle hétérocycloalkyle condensé à 5, 6 ou 7 chaînons, un cycle hétéroaryle condensé à 5 à 6 chaînons ou un cycle C5-6-cycloalkyle condensé, le cycle hétérocycloalkyle condensé à 5, 6 ou 7 chaînons et le cycle hétéroaryle condensé à 5 ou 6 chaînons possédant chacun 1 à 4 hétéroatomes en tant qu'éléments de cycle choisis parmi N, O et S, et le cycle phényle condensé, le cycle hétérocycloalkyle condensé à 5, 6 ou 7 chaînons, le cycle hétéroaryle condensé à 5 à 6 chaînons et le cycle C5-6-cycloalkyle condensé étant chacun éventuellement substitués par 1 ou 2 substituants Rq indépendamment choisis ;
    chaque Ra étant indépendamment choisi parmi H, CN, C1-6-alkyle, C1-4-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons) -C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, les C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à cinq à 10 chaînons) -C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons)-C1-4-alkyle- de Ra étant chacun éventuellement substitués par 1, 2, 3, 4 ou 5 substituants Rd ;
    chaque Rd étant indépendamment choisi parmi C1-4-alkyle, C1-4-halogénoalkyle, halogéno, C3-10-cycloalkyle, hétérocycloalkyle à 4 à 10 chaînons, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe et S(O)2NReRe, les C1-4-alkyle, C3-10-cycloalkyle et hétérocycloalkyle à 4 à 10 chaînons de Rd étant chacun en outre éventuellement substitués par 1 à 3 substituants Rq indépendamment choisis ;
    chaque substituant Rb étant indépendamment choisi parmi halogéno, C1-4-alkyle, C1-4-halogénoalkyle, C1-4-halogénoalcoxy, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons) -C1-4-alkyle-, (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc et S(O)2NRcRc ; les C1-4-alkyle, C1-4-halogénoalkyle, C1-4-halogénoalcoxy, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons) C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de Rb étant chacun en outre éventuellement substitués par 1 à 3 substituants Rd indépendamment choisis ;
    chaque Rc étant indépendamment choisi parmi H, C1-6-alkyle, C1-4-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, les C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons)C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de Rc étant chacun éventuellement substitués par 1, 2, 3, 4 ou 5 substituants Rf indépendamment choisis parmi C1-4-alkyle, C1-4-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons) -C1-4-alkyle-, (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, halogéno, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg) NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg et S(O)2NRgRg, les C1-4-alkyle, C1-4-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à cinq à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de Rf étant chacun éventuellement substitués par 1, 2, 3, 4 ou 5 substituants Rn indépendamment choisis parmi C1-4-alkyle, C1-4-halogénoalkyle, halogéno, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo et S(O)2NRoRo ;
    chaque Rg étant indépendamment choisi parmi H, C1-6-alkyle, C1-4-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) -C1-4-alkyle-, les C1-6-alkyle, C2-6-alcényle, C2-6-alcynyle, C6-10-aryle, C3-10-cycloalkyle, hétéroaryle à 5 à 10 chaînons, hétérocycloalkyle à 4 à 10 chaînons, C6-10-aryl-C1-4-alkyle-, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 10 chaînons) C1-4-alkyle- et (hétérocycloalkyle à 4 à 10 chaînons) C1-4-alkyle- de Rg étant chacun éventuellement substitués par 1 à 3 substituants RP ;
    ou deux substituants quelconques Ra conjointement avec l'atome d'azote auquel ils sont fixés formant un groupe hétérocycloalkyle à 4, 5, 7, 8, 9 ou 10 chaînons éventuellement substitué par 1, 2 ou 3 substituants Rh indépendamment choisis parmi C1-6-alkyle, C3-10-cycloalkyle, hétérocycloalkyle à 4 à 7 chaînons, C6-10-aryle, hétéroaryle à 5 à 6 chaînons, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 6 chaînons) -C1-4-alkyle-, (hétérocycloalkyle à 4 à 7 chaînons) -C1-4-alkyle-, C1-6-halogénoalkyle, C2-6-alcényle, C2-6-alcynyle, halogéno, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi et S(O)2NRiRi, les C1-6-alkyle, C3-10-cycloalkyle, hétérocycloalkyle à 4 à 7 chaînons, C6-10-aryle, hétéroaryle à 5 à 6 chaînons, C3-10-cycloalkyl-C1-4-alkyle-, (hétéroaryle à 5 à 6 chaînons)-C1-4-alkyle- et (hétérocycloalkyle à 4 à 7 chaînons) C1-4-alkyle- de Rh étant chacun en outre éventuellement substitués par 1, 2 ou 3 substituants Rj indépendamment choisis parmi C3-6-cycloalkyle, C6-10-aryle, hétéroaryle à 5 ou 6 chaînons, C2-4-alcényle, C2-4-alcynyle, halogéno, C1-4-alkyle, C1-4-halogénoalkyle, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC (O)NRkRk, NRkC (O)ORk, C(=NRk)NRkRk, NRkC (=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk et S(O)2NRkRk; ou deux groupes Rh fixés au même atome de carbone de l'hétérocycloalkyle à 4 à 10 chaînons, pris ensemble avec l'atome de carbone auxquels ils sont fixés formant un C3-6-cycloalkyle ou hétérocycloalkyle à 4 à 6 chaînons possédant 1 à 2 hétéroatomes en tant qu'éléments de cycle choisis parmi O, N et S ;
    ou deux substituants quelconques Rc conjointement avec l'atome d'azote auquel ils sont fixés formant un groupe hétérocycloalkyle à 4, 5, 6 ou 7 chaînons éventuellement substitué par 1, 2 ou 3 substituants Rh indépendamment choisis ;
    ou deux substituants quelconques Re conjointement avec l'atome d'azote auquel ils sont fixés formant un groupe hétérocycloalkyle à 4, 5, 6 ou 7 chaînons éventuellement substitué par 1, 2 ou 3 substituants Rh indépendamment choisis ;
    ou deux substituants quelconques Rg conjointement avec l'atome d'azote auquel ils sont fixés formant un groupe hétérocycloalkyle à 4, 5, 6 ou 7 chaînons éventuellement substitué par 1, 2 ou 3 substituants Rh indépendamment choisis ;
    ou deux substituants quelconques Ro conjointement avec l'atome d'azote auquel ils sont fixés formant un groupe hétérocycloalkyle à 4, 5, 6 ou 7 chaînons éventuellement substitué par 1, 2 ou 3 substituants Rh indépendamment choisis ;
    chaque Re, Ri, Rk, Ro ou RP étant indépendamment choisi parmi H, C1-4-alkyle, C3-6-cycloalkyle, C6-10-aryle, hétéroaryle à 5 ou 6 chaînons, C1-4-halogénoalkyle, C2-4-alcényle et C2-4-alcynyle, les C1-4-alkyle, C3-6-cycloalkyle, C6-10-aryle, hétéroaryle à 5 ou 6 chaînons, C2-4-alcényle et C2-4-alcynyle de Re, Ri, Rk, Ro ou RP étant chacun éventuellement substitués par 1, 2 ou 3 substituants Rq ;
    chaque Rq étant indépendamment choisi parmi OH, CN, -COOH, NH2, halogéno, C1-4-alkyle, C1-4-alcoxy, C1-4-alkylthio, phényle, hétéroaryle à 5 à 6 chaînons, C3-6-cycloalkyle, NHR12, NR12R12 et C1-4-halogénoalcoxy, les C1-4-alkyle, phényle et hétéroaryle à 5 à 6 chaînons de Rq étant chacun éventuellement substitués par OH, CN, -COOH, NH2, C1-4-alcoxy, C3-10-cycloalkyle et hétérocycloalkyle à 4 à 6 chaînons et chaque R12 étant indépendamment C1-6-alkyle ;
    Figure imgb0127
    étant une simple liaison ou une double liaison pour maintenir le cycle A comme étant aromatique ;
    l'indice n étant un entier parmi 1, 2, 3, 4 ou 5 ; et l'indice m étant un entier parmi 1, 2 ou 3.
  2. Composé selon la revendication 1, possédant la formule (III) :
    Figure imgb0128
     ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant.
  3. Composé selon la revendication 1, possédant la formule (IV) :
    Figure imgb0129
     ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant.
  4. Composé selon la revendication 1, possédant la formule (V) :
    Figure imgb0130
     ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant.
  5. Composé selon la revendication 1, possédant la formule (VI) :
    Figure imgb0131
     ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant.
  6. Composé selon l'une quelconque des revendications 1 à 5 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, le groupement :
    Figure imgb0132
     étant choisi parmi :
    Figure imgb0133
    Figure imgb0134
    Figure imgb0135
  7. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X3, X5 et X6 étant chacun CH, Y1 étant N et Y2 étant C.
  8. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant CH, X2 étant CH, X3, X5 et X6 étant chacun CH, Y1 étant C et Y2 étant N.
  9. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant CH, X2 étant CH, X3 et X6 étant chacun CH, X5 étant N, Y1 étant C et Y2 étant N.
  10. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X3 et X6 étant chacun N, X5 étant CH, Y1 étant N et Y2 étant C.
  11. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X3 et X5 étant chacun CH, X6 étant N, Y1 étant N et Y2 étant C.
  12. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X3 et X6 étant chacun CH, X5 étant N, Y1 étant N et Y2 étant C.
  13. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X5 et X6 étant chacun CH, X3 étant N, Y1 étant N et Y2 étant C.
  14. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 et X2 étant chacun N, X3, X5 et X6 étant chacun CH, Y1 étant C et Y2 étant N.
  15. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 et X2 étant chacun N, X3 étant CH, X5 étant N, X6 étant CR6, Y1 étant C et Y2 étant N.
  16. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 étant N, X2 étant CH, X3 et X5 étant chacun CH, X6 étant CR6, Y1 étant N et Y2 étant C.
  17. Composé selon l'une quelconque des revendications 1 à 6 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, X1 et X2 étant N, X3 et X5 étant chacun CH, X6 étant CR6, Y1 étant N et Y2 étant C.
  18. Composé selon l'une quelconque des revendications 1 à 17 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, R4 étant -CH2-Rb.
  19. Composé selon la revendication 18 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, Rb étant -NRcRc.
  20. Composé selon l'une quelconque des revendications 1 à 19 ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant, R4 étant 2-hydroxyéthylaminométhyle, 2-hydroxyéthyl(méthyl)aminométhyle, 2-carboxypipéridin-1-ylméthyle, (cyanométhyl)aminométhyle, (S)-2-carboxy-pipéridin-1-ylméthyle ou (R)-2-carboxypipéridin-1-ylméthyle.
  21. Composé selon la revendication 1, ou sel pharmaceutiquement acceptable correspondant, le composé étant choisi parmi :
    2-({[2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyridin-6-yl]méthyl}amino)éthanol ;
    2-({[2-(2-méthylbiphényl-3-yl)indolizin-7-yl]méthyl}-amino)éthanol ;
    acide (2S)-1-{[2-(2-méthylbiphényl-3-yl)indolizin-7-yl]méthyl}pipéridin-2-carboxylique ;
    acide (2S)-1-{[6-(2-méthylbiphényl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]méthyl}pipéridin-2-carboxylique ;
    2-((6-(2-méthylbiphényl-3-yl)imidazo[1,2-b]-[1,2,4]triazin-2-yl)méthylamino)éthanol ;
    2-((6-(2-méthylbiphényl-3-yl)imidazo[1,2-b]-[1,2,4]triazin-2-yl)méthylamino)acétonitrile ;
    2-((6-(2-méthylbiphényl-3-yl)imidazo[1,2-b]-[1,2,4]triazin-2-yl)méthylamino)acétamide ;
    2-(méthyl((6-(2-méthylbiphényl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)méthyl)amino)éthanol ;
    2-((8-méthyl-2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyridin-6-yl)méthylamino)éthanol ;
    acide (S)-1-((8-méthyl-2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyridin-6-yl)méthyl)pipéridin-2-carboxylique ;
    2-((8-chloro-2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyridin-6-yl)méthylamino)éthanol ;
    2-({[2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]méthyl}amino)éthanol ;
    2-({[2-(2-méthylbiphényl-3-yl)imidazo[1,2-a]pyrazin-6-yl]méthyl}amino)éthanol ;
    acide (S)-1-((2-(2-méthylbiphényl-3-yl)imidazo[1,2-b]pyridazin-6-yl)méthyl)pipéridine-2-carboxylique ;
    2-({[2-(2-méthylbiphényl-3-yl)imidazo[1,2-b]pyridazin-6-yl]méthyl}amino)éthanol ;
    2-({[2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]méthyl}amino)éthanol ;
    acide (2S)-1-{[2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]méthyl}pipéridin-2-carboxylique ;
    2-({[2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]méthyl}amino)éthanol ;
    acide (2S)-1-{[2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]méthyl}pipéridin-2-carboxylique et
    2-({[5-méthyl-2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo-[1,5-c]pyrimidin-7-yl]méthyl}amino)éthanol.
  22. Composé selon la revendication 1, ou sel pharmaceutiquement acceptable correspondant, le composé étant choisi parmi :
    2-({[8-chloro-2-(2-méthylbiphényl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]méthyl}amino)éthanol ;
    2-({[8-[(2-méthoxyéthyl)amino]-2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]méthyl}amino)-éthanol ;
    4-[6-{[(2-hydroxyéthyl)amino]méthyl}-2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]butanenitrile ;
    [6-{[(2-hydroxyéthyl)amino]méthyl}-2-(2-méthylbiphényl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]acétonitrile ;
    2-(8-chloro-6-{[(2-hydroxyéthyl)amino]méthyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile ;
    2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phényl]-6-{[(2-hydroxyéthyl)amino]méthyl}[1,2,4]triazolo[1,5-a]pyridin-8-carbonitrile et
    2-(8-(cyanométhyl)-6-{[(2-hydroxyéthyl)amino]méthyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile.
  23. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 20, ou un sel pharmaceutiquement acceptable ou un stéréoisomère correspondant, ou un composé selon la revendication 21 ou 22, ou un sel pharmaceutiquement acceptable correspondant.
  24. Composé selon l'une quelconque des revendications 1 à 20, ou sel pharmaceutiquement acceptable ou stéréoisomère correspondant ; ou composé selon la revendication 21 ou 22, ou sel pharmaceutiquement acceptable correspondant ; ou composition selon la revendication 23 pour une utilisation dans le traitement d'une maladie ou d'un trouble associé(e) à l'inhibition de l'interaction PD-1/PD-L1, la maladie ou le trouble étant un cancer ou une infection.
  25. Composé, sel, stéréoisomère ou composition pour une utilisation selon la revendication 24, la maladie ou le trouble étant une infection virale.
  26. Composé, sel, stéréoisomère ou composition pour une utilisation selon la revendication 24, la maladie ou le trouble étant un cancer.
  27. Composé, sel, stéréoisomère ou composition pour une utilisation selon la revendication 26,
    (a) le cancer étant choisi parmi un cancer des os, un cancer du pancréas, un cancer de la peau, un cancer de la tête ou du cou, un mélanome malin cutané ou intraoculaire, un cancer utérin, un cancer de l'ovaire, un cancer rectal, un cancer de la zone anale, un cancer de l'estomac, un cancer testiculaire, un carcinome des trompes de Fallope, un carcinome de l'endomètre, un carcinome du col de l'utérus, un carcinome du vagin, un carcinome de la vulve, un lymphome non hodgkinien, un cancer de l'œsophage, un cancer du petit intestin, un cancer du système endocrinien, un cancer de la glande thyroïde, un cancer de la glande parathyroïde, un cancer de la glande surrénale, un sarcome de tissu mou, un cancer de l'urètre, un cancer du pénis, des leucémies chroniques ou aiguës, des tumeurs solides d'enfance, un lymphome lymphocytaire, un cancer de la vessie, un cancer du rein, un carcinome du pelvis rénal, un néoplasme du système nerveux central (SNC), un lymphome du système nerveux central (SNC) primaire, une angiogenèse de tumeur, une tumeur de l'axe rachidien, un gliome du tronc cérébral, un adénome pituitaire, un sarcome de Kaposi, un cancer épidermoïde, un cancer à cellules squameuses, un lymphome à cellules T, des cancers induits de manière environnementale y compris ceux induits par l'amiante, un mélanome, un mélanome malin métastatique, un cancer rénal, un carcinome à cellules claires, un cancer de la prostate, un adénocarcinome de la prostate réfractaire aux hormones, un cancer du sein, un cancer du côlon, un cancer du poumon, un cancer du poumon non à petites cellules, des tumeurs solides, un cancer de l'œsophage, un cancer hépatique, un cancer gastrique, un cancer de la tête et du cou, un cancer de la thyroïde, un glioblastome, un sarcome, un cancer de la vessie, des cancers hématologiques, un lymphome, une leucémie, une leucémie lymphoblastique aiguë (LLA), une leucémie myélogène aiguë (LMA), une leucémie lymphocytaire chronique (LLC), une leucémie myélogène chronique (LMC), un lymphome diffus à grandes cellules B (DLBCL), un lymphome à cellules du manteau, un lymphome non hodgkinien (LNH), un lymphome non hodgkinien (LNH) récidivant ou réfractaire, un lymphome folliculaire non hodgkinien (LNH) récurrent, un lymphome hodgkinien et un myélome multiple ; ou
    (b) le cancer étant un cancer métastatique qui exprime PD-L1 ; ou
    (c) le cancer étant un cancer du poumon ; ou
    (d) le cancer étant un cancer du poumon non à petites cellules ; ou
    (e) le cancer étant un cancer du rein ; ou
    (f) le cancer étant un cancer hépatique ; ou
    (g) le cancer étant un mélanome ; ou
    (h) le cancer étant un cancer de la vessie ; ou
    (i) le cancer étant un cancer de l'urètre ; ou
    (j) le cancer étant un cancer rénal ; ou
    (k) le cancer étant un carcinome de cellules rénales à cellules claires.
EP16787687.9A 2015-10-19 2016-10-18 Composés hétérocycliques utilisés comme immunomodulateurs Active EP3365340B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562243307P 2015-10-19 2015-10-19
US201662322949P 2016-04-15 2016-04-15
US201662385053P 2016-09-08 2016-09-08
PCT/US2016/057487 WO2017070089A1 (fr) 2015-10-19 2016-10-18 Composés hétérocycliques utilisés comme immunomodulateurs

Publications (2)

Publication Number Publication Date
EP3365340A1 EP3365340A1 (fr) 2018-08-29
EP3365340B1 true EP3365340B1 (fr) 2022-08-10

Family

ID=57206446

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16787687.9A Active EP3365340B1 (fr) 2015-10-19 2016-10-18 Composés hétérocycliques utilisés comme immunomodulateurs

Country Status (6)

Country Link
US (3) US20170107216A1 (fr)
EP (1) EP3365340B1 (fr)
ES (1) ES2928164T3 (fr)
MA (1) MA52119A (fr)
TW (1) TW201718581A (fr)
WO (1) WO2017070089A1 (fr)

Families Citing this family (178)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
PT3176170T (pt) 2012-06-13 2019-02-05 Incyte Holdings Corp Compostos tricíclicos substituídos como inibidores de fgfr
PH12015502383B1 (en) 2013-04-19 2023-02-03 Incyte Holdings Corp Bicyclic heterocycles as fgfr inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2016134320A1 (fr) 2015-02-20 2016-08-25 Incyte Corporation Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr
TW201718581A (zh) 2015-10-19 2017-06-01 英塞特公司 作為免疫調節劑之雜環化合物
WO2017087777A1 (fr) 2015-11-19 2017-05-26 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
US20170174679A1 (en) 2015-12-22 2017-06-22 Incyte Corporation Heterocyclic compounds as immunomodulators
EP3452476B1 (fr) 2016-05-06 2021-12-15 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
WO2017205464A1 (fr) 2016-05-26 2017-11-30 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
SMT202200392T1 (it) 2016-06-20 2022-11-18 Incyte Corp Composti eterociclici come immunomodulatori
ES2979332T3 (es) 2016-06-27 2024-09-25 Chemocentryx Inc Compuestos inmunomoduladores
ES2930092T3 (es) 2016-07-14 2022-12-07 Incyte Corp Compuestos heterocíclicos como inmunomoduladores
WO2018044783A1 (fr) 2016-08-29 2018-03-08 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
AU2017342536A1 (en) 2016-10-14 2019-05-02 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the Hepatitis B virus genome
EP3558963B1 (fr) 2016-12-22 2022-03-23 Incyte Corporation Composés hétéroaromatiques bicycliques utilisés en tant qu'immunomodulateurs
US20180179179A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
CN110267953B (zh) 2016-12-22 2022-12-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
ES2934230T3 (es) 2016-12-22 2023-02-20 Incyte Corp Derivados de benzooxazol como inmunomoduladores
EP3558989B1 (fr) 2016-12-22 2021-04-14 Incyte Corporation Dérivés de triazolo[1,5-a]pyridine en tant qu'immunomodulateurs
CA3061898A1 (fr) 2016-12-28 2019-10-29 Green Cross Lab Cell Corporation Recepteur antigenique chimerique et cellules tueuses naturelles exprimant celui-ci
JOP20180040A1 (ar) 2017-04-20 2019-01-30 Gilead Sciences Inc مثبطات pd-1/pd-l1
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
KR102647257B1 (ko) * 2017-07-28 2024-03-13 케모센트릭스, 인크. 면역조절제 화합물
MA49859A (fr) 2017-08-08 2021-04-07 Chemocentryx Inc Immunomodulateurs macrocycliques
CN111655732B (zh) 2017-11-14 2023-09-12 Gc细胞治疗 抗her2抗体或其抗原结合片段及包含其的嵌合抗原受体
US11649294B2 (en) 2017-11-14 2023-05-16 GC Cell Corporation Anti-HER2 antibody or antigen-binding fragment thereof, and chimeric antigen receptor comprising same
EP3728282B1 (fr) 2017-12-20 2023-11-22 Institute of Organic Chemistry and Biochemistry ASCR, V.V.I. Dinucléotides 2'3' cycliques ayant une liaison phosphonate activant la protéine adaptatrice de sting
CA3084569A1 (fr) 2017-12-20 2019-06-27 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucleotides 3'3' cycliques ayant une liaison phosphonate activant la proteine adaptatrice de sting
AU2019222644B2 (en) 2018-02-13 2021-04-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
MA51232A (fr) 2018-02-22 2020-10-07 Chemocentryx Inc Indane-amines utiles en tant qu'antagonistes de pd-l1
PL3759109T3 (pl) 2018-02-26 2024-03-04 Gilead Sciences, Inc. Podstawione związki pirolizyny jako inhibitory replikacji hbv
WO2019168847A1 (fr) 2018-02-27 2019-09-06 Incyte Corporation Imidazopyrimidines et triazolopyrimidines en tant qu'inhibiteurs a2a/a2b
CA3093851A1 (fr) 2018-03-29 2019-10-03 Arbutus Biopharma Corporation Composes 1,1'-biphenyle substitues, analogues de ceux-ci, et procedes les utilisant
PL3774791T3 (pl) 2018-03-30 2023-06-05 Incyte Corporation Związki heterocykliczne jako immunomodulatory
US10870691B2 (en) 2018-04-05 2020-12-22 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis B virus protein X
TW202005654A (zh) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 ２，２，─環二核苷酸
TWI833744B (zh) 2018-04-06 2024-03-01 捷克科學院有機化學與生物化學研究所 3'3'-環二核苷酸
TWI818007B (zh) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-環二核苷酸
TW201945388A (zh) 2018-04-12 2019-12-01 美商精密生物科學公司 對b型肝炎病毒基因體中之識別序列具有特異性之最佳化之經工程化巨核酸酶
CN112041311B (zh) 2018-04-19 2023-10-03 吉利德科学公司 Pd-1/pd-l1抑制剂
US20190359645A1 (en) 2018-05-03 2019-11-28 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides comprising carbocyclic nucleotide
EP3788046A1 (fr) 2018-05-04 2021-03-10 Incyte Corporation Sels d'un inhibiteur de fgfr
IL312465A (en) 2018-05-04 2024-06-01 Incyte Corp FGFR inhibitor solid forms and processes for their preparation
TWI821288B (zh) 2018-05-11 2023-11-11 美商英塞特公司 作為免疫調節劑之雜環化合物
EP3810610A1 (fr) 2018-05-18 2021-04-28 Incyte Corporation Dérivés de pyrimidine fusionnés utilisés en tant qu'inhibiteurs de a2a/a2b
BR112020024404A2 (pt) 2018-05-31 2021-03-02 Ono Pharmaceutical Co., Ltd. biomarcadores para determinar a eficácia de inibidores de checkpoint imunológico
WO2019232319A1 (fr) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions et procédés d'inhibition de cd73
IL300821B2 (en) 2018-07-05 2025-05-01 Incyte Holdings Corp Fused pyrazine derivatives as A2A/A2B inhibitors
US20220119411A1 (en) * 2018-07-12 2022-04-21 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods thereof
ES2962674T3 (es) 2018-07-13 2024-03-20 Gilead Sciences Inc Inhibidores PD-1/PD-L1
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
WO2020068729A1 (fr) 2018-09-25 2020-04-02 Incyte Corporation Composés pyrazolo[4,3-d]pyrimidine en tant que modulateurs des alk2 et/ou fgfr
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
TWI855000B (zh) 2018-10-11 2024-09-11 日商小野藥品工業股份有限公司 Ｓｔｉｎｇ促效化合物
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
BR112021008255A2 (pt) 2018-10-31 2021-08-03 Gilead Sciences, Inc. compostos de 6-azabenzimidazol substituídos como inibidores de hpk1
JP7273172B2 (ja) 2018-10-31 2023-05-12 ギリアード サイエンシーズ， インコーポレイテッド Ｈｐｋ１阻害活性を有する置換６－アザベンゾイミダゾール化合物
JP2022513592A (ja) 2018-11-02 2022-02-09 シャンハイ マキシノベル ファーマシューティカルズ カンパニー リミテッド ビフェニル系化合物、その中間体、製造方法、医薬組成物及び使用
JP7414827B2 (ja) 2018-12-20 2024-01-16 インサイト・コーポレイション アクチビン受容体様キナーゼ－２の阻害剤としてのイミダゾピリダジン及びイミダゾピリジン化合物
TWI829857B (zh) 2019-01-29 2024-01-21 美商英塞特公司 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶
CN109776377B (zh) * 2019-02-01 2021-08-24 沈阳药科大学 吲哚啉类化合物及其制备方法和应用
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
PH12021551976A1 (en) 2019-02-15 2022-07-04 Incyte Corp Cyclin-dependent kinase 2 biomarkers and uses thereof
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
CA3129011C (fr) 2019-03-07 2023-12-19 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucleotides 3'3'-cycliques et leurs promedicaments
AU2020231201B2 (en) 2019-03-07 2025-02-20 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020185532A1 (fr) 2019-03-08 2020-09-17 Incyte Corporation Méthodes de traitement du cancer au moyen d'un inhibiteur de fgfr
AU2020246317A1 (en) 2019-03-22 2021-11-18 Guangzhou Maxinovel Pharmaceuticals Co., Ltd Small-molecule inhibitor of PD-1/PD-L1, pharmaceutical composition thereof with PD-L1 antibody, and application of same
WO2020205560A1 (fr) 2019-03-29 2020-10-08 Incyte Corporation Composés sulfonylamides utilisés comme inhibiteurs de la cdk2
TW202212339A (zh) 2019-04-17 2022-04-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2020223469A1 (fr) 2019-05-01 2020-11-05 Incyte Corporation Dérivés de n-(1-(méthylsulfonyl)pipéridin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine et composés apparentés utilisés en tant qu'inhibiteurs de kinase 2 dépendante des cyclines (cdk2) pour le traitement du cancer
IL287843B2 (en) 2019-05-15 2025-05-01 Chemocentryx Inc Triaryl compounds for the treatment of PD-L1 diseases
TWI826690B (zh) 2019-05-23 2023-12-21 美商基利科學股份有限公司 經取代之烯吲哚酮化物及其用途
AU2020294781B2 (en) 2019-06-20 2025-10-09 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
WO2021007269A1 (fr) 2019-07-09 2021-01-14 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
JP7747614B2 (ja) 2019-07-10 2025-10-01 ケモセントリックス，インコーポレイティド Ｐｄ－ｌ１阻害剤としてのインダン
WO2021011891A1 (fr) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Formulations à action prolongée de ténofovir alafénamide
CN114206386A (zh) 2019-08-05 2022-03-18 小野药品工业株式会社 免疫检查点抑制剂的有效性判定生物标记
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
CN116348458A (zh) 2019-08-14 2023-06-27 因赛特公司 作为cdk2抑制剂的咪唑基嘧啶基胺化合物
EP4017476A1 (fr) 2019-08-19 2022-06-29 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
CN119770638A (zh) 2019-09-30 2025-04-08 吉利德科学公司 Hbv疫苗和治疗hbv的方法
JP7559059B2 (ja) 2019-09-30 2024-10-01 インサイト・コーポレイション 免疫調節剤としてのピリド［３，２－ｄ］ピリミジン化合物
WO2021067374A1 (fr) 2019-10-01 2021-04-08 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
CN119930610A (zh) 2019-10-11 2025-05-06 因赛特公司 作为cdk2抑制剂的双环胺
BR112022007163A2 (pt) 2019-10-14 2022-08-23 Incyte Corp Heterociclos bicíclicos como inibidores de fgfr
MX2022004450A (es) 2019-10-16 2022-05-03 Chemocentryx Inc Aminas de heteroaril-bifenilo para el tratamiento de enfermedades pd-l1.
WO2021076728A1 (fr) 2019-10-16 2021-04-22 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
PH12022550876A1 (en) 2019-10-16 2023-03-27 Chemocentryx Inc Heteroaryl-biphenyl amides for the treatment of pd-l1 diseases
US20220378761A1 (en) * 2019-11-07 2022-12-01 The Regents Of The University Of Colorado, A Body Corporate PAPD5 Inhibition As A Treatment For Dyskeratosis Congenita, Aplastic Anemia And Myelodysplastic Syndrome Caused By Reduced Telomerase RNA Levels
CR20220237A (es) 2019-11-11 2022-08-05 Incyte Corp Sales y formas cristalinas de un inhibidor de pd-1/pd-l1
CA3163875A1 (fr) 2019-12-04 2021-06-10 Incyte Corporation Heterocycles tricycliques en tant qu'inhibiteurs de fgfr
CR20220285A (es) 2019-12-04 2022-10-27 Incyte Corp Derivados de un inhibidor de fgfr
CN116057068A (zh) 2019-12-06 2023-05-02 精密生物科学公司 对乙型肝炎病毒基因组中的识别序列具有特异性的优化的工程化大范围核酸酶
EP4085060A1 (fr) 2020-01-03 2022-11-09 Incyte Corporation Polythérapie comprenant des inhibiteurs d'a2a/a2b et de pd-1/pd-l1
CA3163389A1 (fr) 2020-01-03 2021-07-08 Mi ZENG Inhibiteur de derive biphenyle, son procede de preparation et son utilisation
KR20220125287A (ko) 2020-01-10 2022-09-14 인사이트 코포레이션 Kras 억제제로서 트리사이클릭 화합물
WO2021146424A1 (fr) 2020-01-15 2021-07-22 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
US11530218B2 (en) 2020-01-20 2022-12-20 Incyte Corporation Spiro compounds as inhibitors of KRAS
TW202140487A (zh) 2020-02-06 2021-11-01 美商英塞特公司 Ｐｉ３ｋ抑制劑之鹽及固體形式以及其製備方法
PH12022552347A1 (en) 2020-03-06 2024-01-29 Incyte Corp Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
CN113493469A (zh) * 2020-03-18 2021-10-12 成都倍特药业股份有限公司 可作为免疫调节剂的化合物、其制备方法和应用
AR121620A1 (es) 2020-03-20 2022-06-22 Gilead Sciences Inc Profármacos de nucleósidos 4’-c-sustituidos-2-halo-2’-deoxiadenosina y métodos de preparación y uso de los mismos
EP4134134A4 (fr) 2020-04-10 2023-12-27 ONO Pharmaceutical Co., Ltd. Composé agoniste de sting
EP4134098A4 (fr) 2020-04-10 2024-05-15 ONO Pharmaceutical Co., Ltd. Méthode de cancérothérapie
IL297165A (en) 2020-04-16 2022-12-01 Incyte Corp Soysag tricyclic CRS inhibitors
WO2021226206A2 (fr) 2020-05-05 2021-11-11 Teon Therapeutics, Inc. Modulateurs de récepteur cannabinoïde de type 2 (cb2) et leurs utilisations
WO2021231526A1 (fr) 2020-05-13 2021-11-18 Incyte Corporation Composés de pyrimidine fusionnés utilisés comme inhibiteurs de kras
KR20230025434A (ko) 2020-06-12 2023-02-21 인사이트 코포레이션 이미다조피리다진 화합물 및 이의 용도
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
WO2021257863A1 (fr) 2020-06-19 2021-12-23 Incyte Corporation Composés de pyrrolotriazine utilisés en tant qu'inhibiteurs de v617f de jak2
MX2023000056A (es) 2020-07-02 2023-04-12 Incyte Corp Compuestos tricíclicos de urea como inhibidores de la variante v617f de la cinasa de janus 2 (jak2 v617f).
WO2022006456A1 (fr) 2020-07-02 2022-01-06 Incyte Corporation Composés de pyridone tricyclique en tant qu'inhibiteurs de v617f de jak2
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11999752B2 (en) 2020-08-28 2024-06-04 Incyte Corporation Vinyl imidazole compounds as inhibitors of KRAS
US20230331675A1 (en) 2020-09-09 2023-10-19 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Aromatic ethylene compound and preparation method therefor, and intermediate, pharmaceutical composition, and application thereof
WO2022072783A1 (fr) 2020-10-02 2022-04-07 Incyte Corporation Composés diones bicycliques en tant qu'inhibiteurs de kras
TW202233615A (zh) 2020-11-06 2022-09-01 美商英塞特公司 Ｐｄ—１／ｐｄ—ｌ１抑制劑之結晶形式
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
WO2022099018A1 (fr) 2020-11-06 2022-05-12 Incyte Corporation Procédé de préparation d'un inhibiteur de pd-1/pd-l1
CN114507227B (zh) * 2020-11-17 2024-06-21 中国医学科学院药物研究所 苯并异噻唑类化合物、及其制法和药物组合物与用途
WO2022140231A1 (fr) 2020-12-21 2022-06-30 Incyte Corporation Composés de déazaguanine utilisés en tant qu'inhibiteurs de v617f de jak2
US20220233529A1 (en) 2020-12-29 2022-07-28 Incyte Corporation Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies
TW202302589A (zh) 2021-02-25 2023-01-16 美商英塞特公司 作為ｊａｋ２ ｖ６１７ｆ抑制劑之螺環內醯胺
WO2022204112A1 (fr) 2021-03-22 2022-09-29 Incyte Corporation Inhibiteurs d'imidazole et triazole kras
CA3215903A1 (fr) 2021-04-12 2022-10-20 Incyte Corporation Polytherapie comprenant un inhibiteur de fgfr et un agent de ciblage de nectine-4
TW202348237A (zh) 2021-05-13 2023-12-16 美商基利科學股份有限公司 TLR8調節化合物及抗HBV siRNA療法之組合
JP2024522189A (ja) 2021-06-09 2024-06-11 インサイト・コーポレイション Ｆｇｆｒ阻害剤としての三環式ヘテロ環
AR126101A1 (es) 2021-06-09 2023-09-13 Incyte Corp Heterociclos tricíclicos como inhibidores de fgfr
CA3222752A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des conjugues anti-corps-medicament
TWI883332B (zh) 2021-06-11 2025-05-11 美商基利科學股份有限公司 Mcl-1抑制劑與抗癌劑之組合
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
CN117377671A (zh) 2021-06-23 2024-01-09 吉利德科学公司 二酰基甘油激酶调节化合物
EP4359415A1 (fr) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
KR20240025616A (ko) 2021-06-23 2024-02-27 길리애드 사이언시즈, 인코포레이티드 다이아실글리세롤 키나제 조절 화합물
US11926628B2 (en) 2021-06-23 2024-03-12 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
MX2024000357A (es) 2021-07-07 2024-02-12 Incyte Corp Compuestos triciclicos como inhibidores de homologo de oncogen viral de sarcoma de rata kirsten (kras).
WO2023287896A1 (fr) 2021-07-14 2023-01-19 Incyte Corporation Composés tricycliques utiles en tant qu'inhibiteurs de kras
JP2024534187A (ja) 2021-08-31 2024-09-18 インサイト・コーポレイション Ｋｒａｓの阻害剤としてのナフチリジン化合物
TW202325306A (zh) 2021-09-02 2023-07-01 美商天恩治療有限公司 改良免疫細胞之生長及功能的方法
CN113773273B (zh) * 2021-09-15 2023-04-11 沈阳药科大学 苯并异噻唑类化合物及其制备方法和用途
US12030883B2 (en) 2021-09-21 2024-07-09 Incyte Corporation Hetero-tricyclic compounds as inhibitors of KRAS
WO2023050104A1 (fr) * 2021-09-28 2023-04-06 中国医学科学院药物研究所 Dérivé d'indoline, son procédé de préparation, composition pharmaceutique et utilisation
WO2023056421A1 (fr) 2021-10-01 2023-04-06 Incyte Corporation Inhibiteurs de kras tels que la pyrazoloquinoline
MX2024004444A (es) 2021-10-14 2024-05-08 Incyte Corp Compuestos de quinolina como inhibidores de la proteina del virus de sarcoma de rata kirsten (kras).
WO2023081730A1 (fr) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. Dérivés de 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphtyridine-3-carboxamide utilisés en tant que modulateurs du récepteur cb2 cannabinoïde pour le traitement du cancer
AU2022389961A1 (en) 2021-11-22 2024-06-06 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a kras inhibitor
WO2023097211A1 (fr) 2021-11-24 2023-06-01 The University Of Southern California Méthodes pour améliorer une thérapie par inhibiteur de point de contrôle immunitaire
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
CA3244187A1 (fr) 2021-12-22 2023-06-29 Incyte Corp Sels et formes solides d'un inhibiteur de fgfr et leurs méthodes de préparation
MX2024011378A (es) 2022-03-17 2024-09-23 Incyte Corp Compuestos de urea triciclica como inhibidores de la variante v617f de la cinasa de janus 2 (jak2).
KR20250007533A (ko) 2022-04-08 2025-01-14 샤이 테라퓨틱스 엘엘씨 암, 염증성 질환, ras질환 및 섬유성 질환의 치료를 위한 ras 슈퍼패밀리 단백질과 상호작용하는 화합물
WO2023239768A1 (fr) 2022-06-08 2023-12-14 Incyte Corporation Composés triazolo tricycliques utilisés comme inhibiteurs de dgk
WO2024015731A1 (fr) 2022-07-11 2024-01-18 Incyte Corporation Composés tricycliques fusionnés en tant qu'inhibiteurs de mutants kras g12v
WO2024015372A1 (fr) 2022-07-14 2024-01-18 Teon Therapeutics, Inc. Antagonistes des récepteurs de l'adénosine et leurs utilisations
TW202417488A (zh) 2022-08-23 2024-05-01 日商小野藥品工業股份有限公司 雙特異性抗體
US20240190876A1 (en) 2022-10-21 2024-06-13 Incyte Corporation Tricyclic Urea Compounds As JAK2 V617F Inhibitors
US20240217989A1 (en) 2022-11-18 2024-07-04 Incyte Corporation Heteroaryl Fluoroalkenes As DGK Inhibitors
WO2024151346A1 (fr) 2023-01-12 2024-07-18 Incyte Corporation Hétéroaryl fluoroalcènes utilisés comme inhibiteurs de dgk
TW202440086A (zh) 2023-03-13 2024-10-16 美商英塞特公司 作為激酶抑制劑之雙環脲
US20240390340A1 (en) 2023-04-18 2024-11-28 Incyte Corporation Pyrrolidine kras inhibitors
US20250066363A1 (en) 2023-08-24 2025-02-27 Incyte Corporation Bicyclic DGK Inhibitors
US20250114346A1 (en) 2023-10-09 2025-04-10 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
WO2025096738A1 (fr) 2023-11-01 2025-05-08 Incyte Corporation Inhibiteurs de kras
US20250179083A1 (en) 2023-12-05 2025-06-05 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
TW202523304A (zh) 2023-12-06 2025-06-16 美商英塞特公司 包含ｄｇｋ抑制劑及ｐｄ—１／ｐｄ—ｌ１抑制劑之組合療法
US20250195536A1 (en) 2023-12-13 2025-06-19 Incyte Corporation Bicyclooctane kras inhibitors
WO2025240242A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec ribavirine
WO2025240246A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec de la ribavirine
WO2025240243A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies comprenant du bulévirtide et un acide nucléique inhibiteur ciblant le virus de l'hépatite b
US20250345390A1 (en) 2024-05-13 2025-11-13 Gilead Sciences, Inc. Combination therapies

Family Cites Families (332)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272781A (en) 1963-08-07 1966-09-13 American Potash & Chem Corp Boroureas of phosphinoborine polymers
FR1425700A (fr) 1965-02-22 1966-01-24 Basf Ag Composés formant des complexes métalliques et procédé pour les préparer et les utiliser
US4208328A (en) 1978-04-27 1980-06-17 General Electric Company Alkyl 3,5-dihydroxy-4-(2-benzothiazolyl)benzoates
US4789711A (en) 1986-12-02 1988-12-06 Ciba-Geigy Corporation Multifunctional epoxide resins
JPH0611031Y2 (ja) 1988-02-27 1994-03-23 タマパック株式会社 ゴルフ用パッティンググリーン
DE3828535A1 (de) 1988-08-23 1990-03-08 Basf Ag Benzimidazol-2-carbonsaeureanilide, ihre verwendung als lichtschutzmittel fuer organisches material und mit diesen aniliden stabilisiertes organisches material
US5077164A (en) 1989-06-21 1991-12-31 Minolta Camera Kabushiki Kaisha Photosensitive member containing an azo dye
DE69421982T2 (de) 1993-09-20 2000-03-30 Fuji Photo Film Co., Ltd. Positiv arbeitende Photoresistzusammensetzung
JP3461397B2 (ja) 1995-01-11 2003-10-27 富士写真フイルム株式会社 ポジ型フオトレジスト組成物
WO1998027108A2 (fr) 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amide
JPH10316853A (ja) 1997-05-15 1998-12-02 Sumitomo Bakelite Co Ltd 半導体多層配線用層間絶縁膜樹脂組成物及び該絶縁膜の製造方法
EP1019391A1 (fr) 1997-10-02 2000-07-19 Merck & Co. Inc. Inhibiteurs de la prenyl-proteine transferase
AU2745899A (en) 1998-03-05 1999-09-20 Nissan Chemical Industries Ltd. Anilide compounds and herbicide
JP2000128984A (ja) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール前駆体及び樹脂
JP2000128986A (ja) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール前駆体及びポリベンゾオキサゾール
JP2000128987A (ja) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール前駆体及びポリベンゾオキサゾール
US6297351B1 (en) 1998-12-17 2001-10-02 Sumitomo Bakelite Company Limited Polybenzoxazole resin and precursor thereof
HUP0104987A3 (en) 1998-12-18 2002-09-30 Axys Pharmaceuticals Inc South Benzimidazole or indole derivatives protease inhibitors, and pharmaceutical compositions containing them
JP2000212281A (ja) 1999-01-27 2000-08-02 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾ―ル前駆体及びポリベンゾオキサゾ―ル樹脂
AU6000900A (en) 1999-07-23 2001-02-13 Astrazeneca Uk Limited Carbazole derivatives and their use as neuropeptide y5 receptor ligands
JP2001114893A (ja) 1999-10-15 2001-04-24 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール樹脂およびその前駆体
US6372907B1 (en) 1999-11-03 2002-04-16 Apptera Corporation Water-soluble rhodamine dye peptide conjugates
JP2001163975A (ja) 1999-12-03 2001-06-19 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール樹脂及びその前駆体
ID30204A (id) 1999-12-27 2001-11-15 Japan Tobacco Inc Senyawa-senyawa cincin terfusi dan penggunaannya sebagai obat
ATE372337T1 (de) 2000-02-01 2007-09-15 Abbott Gmbh & Co Kg Heterozyklische verbindungen und deren anwendung als parp-inhibitoren
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
US6908929B2 (en) 2000-03-31 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
CA2405170A1 (fr) 2000-04-24 2001-11-01 Merck Frosst Canada & Co. Methode de traitement se basant sur l'utilisation de derives de phenyle et de biaryle comme inhibiteurs de prostaglandine e
MXPA03000051A (es) 2000-06-28 2003-08-19 Smithkline Beecham Plc Procedimiento de molido en humedo.
AU2001294515A1 (en) 2000-08-11 2002-02-25 The Regents Of The University Of California Use of stat-6 inhibitors as therapeutic agents
EP1343785A2 (fr) 2000-12-13 2003-09-17 Basf Aktiengesellschaft Utilisation d'imidazoazines substituees, nouvelles imidazoazines, procede permettant de les produire et agents les contenant
ES2245380T3 (es) 2000-12-15 2006-01-01 Glaxo Group Limited Pirazolopiridinas.
SE0100567D0 (sv) 2001-02-20 2001-02-20 Astrazeneca Ab Compounds
WO2002071827A2 (fr) 2001-03-14 2002-09-19 Eli Lilly And Company Modulateurs des recepteurs x de retinoides
JP4237497B2 (ja) 2001-03-30 2009-03-11 スミスクライン ビーチャム コーポレーション ピラゾロピリジン類、その調製方法及びその治療用化合物としての使用
ES2266487T3 (es) 2001-04-10 2007-03-01 Smithkline Beecham Corporation Compuestos de pirazolopirina antivirales.
JP2002316966A (ja) 2001-04-19 2002-10-31 Ueno Seiyaku Oyo Kenkyusho:Kk ビナフトール誘導体およびその製法
AU2002305143A1 (en) 2001-04-27 2002-11-11 Smithkline Beecham Corporation Pyrazolo'1,5-a!pyridine derivatives
AR035543A1 (es) 2001-06-26 2004-06-16 Japan Tobacco Inc Agente terapeutico para la hepatitis c que comprende un compuesto de anillo condensado, compuesto de anillo condensado, composicion farmaceutica que lo comprende, compuestos de benzimidazol, tiazol y bifenilo utiles como intermediarios para producir dichos compuestos, uso del compuesto de anillo con
ES2286272T3 (es) 2001-09-07 2007-12-01 Smithkline Beecham Corporation Pirizolo-piridinas para el tratamiento de infecciones por herpes.
TWI320039B (en) 2001-09-21 2010-02-01 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US6727274B2 (en) 2001-10-09 2004-04-27 Pharmacia & Upjohn Company Arylsulphonyl substituted-tetrahydro- and hexahydro-carbazoles
US20030143199A1 (en) 2001-10-09 2003-07-31 Carson Dennis A. Use of STAT-6 inhibitors as therapeutic agents
JP4024579B2 (ja) 2002-01-22 2007-12-19 住友ベークライト株式会社 プラスチック光導波路用材料及び光導波路
RU2004133044A (ru) 2002-04-11 2006-01-27 Вертекс Фармасьютикалз Инкорпорейтед (Us) Ингибиторы сериновых протеаз, в частности, протеазы ns3-ns4a hcv
JP4500055B2 (ja) 2002-04-23 2010-07-14 塩野義製薬株式会社 ピラゾロ［１，５−ａ］ピリミジン誘導体およびそれを含有するＮＡＤ（Ｐ）Ｈオキシダーゼ阻害剤
WO2004007472A1 (fr) 2002-07-10 2004-01-22 Ono Pharmaceutical Co., Ltd. Antagoniste du ccr4 et utilisation medicinale correspondante
WO2004006906A2 (fr) 2002-07-15 2004-01-22 Combinatorx, Incorporated Methodes de traitement de neoplasmes
JP2004059761A (ja) 2002-07-30 2004-02-26 Sumitomo Bakelite Co Ltd ポリベンゾオキサゾール樹脂、その前駆体及びこれらを用いた光導波路材料並びに光導波路
JP2004091369A (ja) 2002-08-30 2004-03-25 Sumitomo Pharmaceut Co Ltd 新規ビフェニル化合物
AU2003261834A1 (en) 2002-08-30 2004-05-04 Bf Research Institute, Inc. Diagnostic probes and remedies for diseases with accumulation of prion protein, and stains for prion protein
EP1546148A1 (fr) 2002-10-03 2005-06-29 SmithKline Beecham Corporation Composes therapeutiques a base de derives de pyrazolopyridine
US7582630B2 (en) 2002-10-15 2009-09-01 Smithkline Beecham Corporation Pyradazine compounds as GSK-3 inhibitors
KR100624406B1 (ko) 2002-12-30 2006-09-18 삼성에스디아이 주식회사 비페닐 유도체 및 이를 채용한 유기 전계 발광 소자
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
AR043633A1 (es) 2003-03-20 2005-08-03 Schering Corp Ligandos de receptores de canabinoides
JP4595288B2 (ja) 2003-03-25 2010-12-08 住友ベークライト株式会社 ポリベンゾオキサゾール樹脂、その前駆体及びこれらを用いた光導波路材料並びに光導波路
AU2004228453B2 (en) 2003-04-11 2010-08-19 Glenmark Pharmaceuticals S.A. Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
CA2524048C (fr) 2003-05-19 2013-06-25 Irm Llc Composes immunosuppresseurs et compositions
JP2005002330A (ja) 2003-05-19 2005-01-06 Sumitomo Electric Ind Ltd 光学樹脂材料、光学素子、光モジュール、フッ素化ポリマー前駆体及びフッ素化ポリマー
US20060183746A1 (en) 2003-06-04 2006-08-17 Currie Kevin S Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
WO2005014599A1 (fr) 2003-06-04 2005-02-17 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines et methodes d'inhibition de la tyrosine kinase de bruton par de tels composes
WO2005005429A1 (fr) 2003-06-30 2005-01-20 Cellular Genomics, Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines substituees heterocycliques et methodes d'inhibition de la tyrosine kinase de bruton utilisant ces composes
CA2531856C (fr) 2003-07-11 2013-07-30 Merck Patent Gesellschaft Mit Beschraenkter Haftung Benzimidazole carboxamides utilises en tant qu'inhibiteurs de la kinase raf
EP1644370A4 (fr) 2003-07-11 2008-06-04 Bristol Myers Squibb Co Derives de tetrahydroquinoleine constituant des modulateurs des recepteurs des cannabinoides
WO2005012221A1 (fr) 2003-08-04 2005-02-10 Ono Pharmaceutical Co., Ltd. Compose d'ether de diphenyle, sa methode de preparation et d'utilisation
WO2005014543A1 (fr) 2003-08-06 2005-02-17 Japan Tobacco Inc. Compose a cycle condense utilise comme inhibiteur de la polymerase du vhc
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
SG146624A1 (en) 2003-09-11 2008-10-30 Kemia Inc Cytokine inhibitors
BRPI0415210A (pt) 2003-10-08 2006-12-05 Irm Llc compostos e composições como inibidores de proteìna cinase
EP1679309A4 (fr) 2003-10-24 2007-03-28 Ono Pharmaceutical Co Medicament antistress et usage medical correspondant
WO2005047290A2 (fr) 2003-11-11 2005-05-26 Cellular Genomics Inc. Certaines imidazo[1,2-a]pyrazin-8-ylamines, procede de fabrication et methode d'utilisation
JP2007534652A (ja) 2003-12-23 2007-11-29 ビーエーエスエフ　アクチェンゲゼルシャフト ３−トリフルオロメチルピコリン酸アニリドおよび殺菌剤としてのその使用
AU2005215379A1 (en) 2004-02-12 2005-09-01 Merck & Co., Inc. Bipyridyl amides as modulators of metabotropic glutamate receptor-5
US20070191395A1 (en) 2004-02-16 2007-08-16 Katsuhiro Kawakami Heterocyclic compounds having antifungal activity
GB0403864D0 (en) 2004-02-20 2004-03-24 Ucl Ventures Modulator
JP2005248082A (ja) 2004-03-05 2005-09-15 Sumitomo Electric Ind Ltd ポリベンゾオキサゾール樹脂前駆体の製造方法およびポリベンゾオキサゾール樹脂の製造方法
EP1722789A2 (fr) 2004-03-08 2006-11-22 Amgen Inc. Modulation therapeutique de l'activite de recepteur de ppar-gamma
JP2007527908A (ja) 2004-03-08 2007-10-04 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 抗原虫薬としての新規ジカチオン性イミダゾ［１，２−ａ］ピリジン、及び５，６，７，８−テトラヒドロ−イミダゾ［１，２−ａ］ピリジン
WO2005097751A2 (fr) 2004-03-31 2005-10-20 Janssen Pharmaceutica, N.V. Composes heterocycliques non-imidazole
JP2005290301A (ja) 2004-04-02 2005-10-20 Sumitomo Electric Ind Ltd ポリベンゾオキサゾール樹脂前駆体の製造方法およびポリベンゾオキサゾール樹脂の製造方法
WO2005099656A2 (fr) 2004-04-06 2005-10-27 The Procter & Gamble Company Composes de teinture de la keratine, compositions de teinture de la keratine contenant ces composes et leurs utilisations
JP4879165B2 (ja) 2004-04-20 2012-02-22 トランス テック ファーマ，インコーポレイテッド メラノコルチン受容体の調節因子としての置換チアゾール及びピリミジン誘導体
DE102004021716A1 (de) 2004-04-30 2005-12-01 Grünenthal GmbH Substituierte Imidazo[1,2-a]pyridin-Verbindungen und Arzneimittel enthaltend substituierte Imidazo[1,2-a]pyridin-Verbindungen
WO2005108387A2 (fr) 2004-05-03 2005-11-17 Boehringer Ingelheim Pharmaceuticals, Inc. Inhibiteurs de cytokines
PE20060748A1 (es) 2004-09-21 2006-10-01 Smithkline Beecham Corp Derivados de indolcarboxamida como inhibidores de quinasa ikk2
CN101035528A (zh) 2004-09-23 2007-09-12 惠氏公司 治疗丙型肝炎病毒感染的咔唑和环戊二烯并吲哚衍生物
WO2006044687A2 (fr) 2004-10-15 2006-04-27 Takeda San Diego, Inc. Inhibiteurs de kinase
BRPI0517619A (pt) 2004-11-10 2008-10-14 Cgi Pharmaceuticals Inc entidades quìmicas de imidazo[1,2-a] pirazin-8-ilaminas, suas composições farmacêuticas, uso dos referidos compostos na preparação de medicamento, processo de preparação de medicamento e métodos de utilização dos referidos compostos
DE102004054665A1 (de) 2004-11-12 2006-05-18 Bayer Cropscience Gmbh Substituierte bi- und tricyclische Pyrazol-Derivate Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren
AU2006218403A1 (en) 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Fused heterocyclic compounds and their use as sirtuin modulators
BRPI0608252A2 (pt) 2005-03-10 2010-04-06 Cgi Pharmaceuticals Inc entidades quìmicas, composições farmacêuticas compreendendo as mesmas, métodos utilizando as referidas entidades quìmicas e uso das referidas entidades quìmicas
JP2006290883A (ja) 2005-03-17 2006-10-26 Nippon Nohyaku Co Ltd 置換ヘテロ環カルボン酸アニリド誘導体、その中間体及び農園芸用薬剤並びにその使用方法
EP1902056A2 (fr) 2005-05-20 2008-03-26 Array Biopharma, Inc. Composes inhibiteurs raf et procedes d'utilisation de ceux-ci
US20080220968A1 (en) 2005-07-05 2008-09-11 Ge Healthcare Bio-Sciences Ab [1, 2, 4] Triazolo [1, 5-A] Pyrimidine Derivatives as Chromatographic Adsorbent for the Selective Adsorption of Igg
WO2007034282A2 (fr) 2005-09-19 2007-03-29 Pfizer Products Inc. Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a
US7723336B2 (en) 2005-09-22 2010-05-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US20070078136A1 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
ES2390135T3 (es) 2005-11-22 2012-11-06 Merck Sharp & Dohme Corp. Compuestos tricíclicos útiles como inhibidores de quinasas
WO2007067711A2 (fr) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certains types d'entites chimiques, compositions et methode de modulation de trpv1
EP1961745A1 (fr) 2005-12-12 2008-08-27 Ono Pharmaceutical Co., Ltd. Compose heterocyclique bicyclique
US20090281075A1 (en) 2006-02-17 2009-11-12 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
WO2007096764A2 (fr) 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
EP1992348A4 (fr) 2006-03-08 2009-09-23 Takeda Pharmaceutical Combinaison pharmaceutique
KR20080104351A (ko) 2006-03-31 2008-12-02 노파르티스 아게 유기 화합물
WO2008118122A2 (fr) 2006-05-08 2008-10-02 Molecular Neuroimaging, Llc Composés et sondes amyloïdes de ceux-ci pour des utilisations thérapeutiques et en imagerie
EP2035005A4 (fr) 2006-06-09 2011-07-06 Kemia Inc Thérapie à base d'inhibiteurs de cytokine
US20080280891A1 (en) 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
WO2008011557A2 (fr) 2006-07-20 2008-01-24 Borchardt Allen J Inhibiteurs hétéroaryliques de la kinase rho
DE102006035018B4 (de) 2006-07-28 2009-07-23 Novaled Ag Oxazol-Triplett-Emitter für OLED-Anwendungen
WO2008021745A2 (fr) 2006-08-16 2008-02-21 Itherx Pharmaceuticals, Inc. Inhibiteurs de la pénétration du virus de l'hépatite c
TWI389895B (zh) 2006-08-21 2013-03-21 Infinity Discovery Inc 抑制ｂｃｌ蛋白質與結合夥伴間之交互作用的化合物及方法
WO2008027812A2 (fr) 2006-08-28 2008-03-06 Forest Laboratories Holdings Limited Dérivés d'imidazopyridine et d'imidazopyrimidine
AR063707A1 (es) 2006-09-11 2009-02-11 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmacéuticas que las comprenden.
US7838523B2 (en) 2006-09-11 2010-11-23 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
EP2068849A2 (fr) 2006-09-11 2009-06-17 CGI Pharmaceuticals, Inc. Inhibiteurs de kinase et procédés d'utilisation et d'identification des inhibiteurs de kinase
MX2009002657A (es) 2006-09-11 2009-08-18 Matrix Lab Ltd Derivados dibenzofurano como inhibidores de pde-4 y pde-10.
AR063706A1 (es) 2006-09-11 2009-02-11 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden.
FR2906250B1 (fr) 2006-09-22 2008-10-31 Sanofi Aventis Sa Derives de 2-aryl-6phenyl-imidazo(1,2-a) pyridines, leur preparation et leur application en therapeutique
MX2009004289A (es) 2006-10-27 2009-05-05 Wyeth Corp Compuestos triciclicos como inhibidores de metaloproteinasas matriciales.
AU2007317296B2 (en) 2006-11-08 2012-07-05 Bristol-Myers Squibb Company Pyridinone compounds
GB0623209D0 (en) 2006-11-21 2007-01-03 F2G Ltd Antifungal agents
WO2008064317A1 (fr) 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Composés actifs de récepteurs opioïdes lipophiles
WO2008064318A2 (fr) 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Composés actifs de récepteurs opioïdes périphériques
WO2008071944A1 (fr) 2006-12-14 2008-06-19 Boehringer Ingelheim International Gmbh Benzoxasoles utiles dans le traitement de l'inflammation
ES2415863T3 (es) 2006-12-22 2013-07-29 Incyte Corporation Heterociclos sustituidos como inhibidores de Janus Quinasas
US8338437B2 (en) 2007-02-28 2012-12-25 Methylgene Inc. Amines as small molecule inhibitors
EP1964840A1 (fr) 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]pyridines et leur utilisation en tant que produits pharmaceutiques
EP1964841A1 (fr) 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]azine et son utilisation en tant que produit pharmaceutique
JP2008218327A (ja) 2007-03-07 2008-09-18 Hitachi Ltd 電解質、電解質膜、それを用いた膜電極接合体、燃料電池電源及び燃料電池電源システム
JP2010120852A (ja) 2007-03-09 2010-06-03 Daiichi Sankyo Co Ltd 新規なジアミド誘導体
CN101679350B (zh) 2007-03-22 2014-03-12 阿斯利康(瑞典)有限公司 用于治疗炎性疾病的喹啉衍生物
TW200902526A (en) 2007-04-24 2009-01-16 Shionogi & Amp Co Ltd Aminodihydrothiazin derivative substituted with a cyclic group
JP5383483B2 (ja) 2007-04-24 2014-01-08 塩野義製薬株式会社 アルツハイマー症治療用医薬組成物
WO2008134553A1 (fr) 2007-04-26 2008-11-06 Xenon Pharmaceuticals Inc. Procédés de traitement de maladies associées aux canaux sodiques au moyen de composés bicycliques
PT2155747E (pt) 2007-05-10 2012-12-19 Ge Healthcare Ltd Imidazol(1,2-a)piridinas e compostos relacionados com actividade nos receptores de canabinóides cb2
WO2009027733A1 (fr) 2007-08-24 2009-03-05 Astrazeneca Ab Dérivés de (2-pyridin-3-ylimidazo[1,2-b]pyridazin-6-yl)urée en tant qu'agents antibactériens
CL2008002793A1 (es) 2007-09-20 2009-09-04 Cgi Pharmaceuticals Inc Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras
US8080542B2 (en) 2007-09-20 2011-12-20 Amgen, Inc. S1P receptor modulating compounds and use thereof
DE102007048716A1 (de) 2007-10-11 2009-04-23 Merck Patent Gmbh Imidazo[1,2-a]pyrimidinderivate
TW200932219A (en) 2007-10-24 2009-08-01 Astellas Pharma Inc Oxadiazolidinedione compound
JP2011500778A (ja) 2007-10-25 2011-01-06 アストラゼネカ・アクチエボラーグ ピリジン及びピラジン誘導体−０８３
US7868001B2 (en) 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
WO2009062059A2 (fr) 2007-11-08 2009-05-14 Pharmacopeia, Inc. Purinones et 1h-imidazopyridinones isomères comme inhibiteurs de pkc-thêta
CA2707491A1 (fr) 2007-12-13 2009-06-18 Merck Sharp & Dohme Corp. Inhibiteurs de janus kinases
RU2364597C1 (ru) 2007-12-14 2009-08-20 Андрей Александрович Иващенко ГЕТЕРОЦИКЛИЧЕСКИЕ ИНГИБИТОРЫ Hh-СИГНАЛЬНОГО КАСКАДА, ЛЕКАРСТВЕННЫЕ КОМПОЗИЦИИ НА ИХ ОСНОВЕ И СПОСОБ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АББЕРАНТНОЙ АКТИВНОСТЬЮ Hh СИГНАЛЬНОЙ СИСТЕМЫ
WO2009077197A1 (fr) 2007-12-19 2009-06-25 Syngenta Participations Ag Composés insecticides
US8642660B2 (en) 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
AU2008340182A1 (en) 2007-12-21 2009-07-02 The University Of Sydney Translocator protein ligands
WO2009091016A1 (fr) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. Dérivé d'aminodihydrothiazine condensée
JP5381718B2 (ja) 2008-01-31 2014-01-08 コニカミノルタ株式会社 ハロ多環芳香族化合物及びその製造方法
CA2714500A1 (fr) 2008-02-26 2009-09-03 Novartis Ag Composes heterocycliques comme inhibiteurs de cxcr2
EP2095818A1 (fr) 2008-02-29 2009-09-02 AEterna Zentaris GmbH Utilisation d'antagonistes LHRH dans des doses n'impliquant pas de castration
FR2928924B1 (fr) 2008-03-21 2010-04-23 Sanofi Aventis Derives polysubstitues de 6-heteroaryle-imidazo°1,2-a! pyridines, leur preparation et leur application en therapeutique
FR2928922B1 (fr) 2008-03-21 2010-04-23 Sanofi Aventis Derives de 2-aryl-6-phenyl-imidazo°1,2-a!pyridines polysubstitues, leur preparation et leur application en therapeutique
FR2928921B1 (fr) 2008-03-21 2010-04-23 Sanofi Aventis Derives polysubstitues de 2-aryl-6-phenyl-imidazo°1,2-a!pyridines, leur preparation et leur application en therapeutique
US8461163B2 (en) 2008-03-31 2013-06-11 Takeda Pharmaceutical Company Limited Substituted N-(pyrazolo[1,5-a]pyrimidin-5-yl)amides as inhibitors of apoptosis signal-regulating kinase 1
KR101034351B1 (ko) 2008-05-14 2011-05-16 한국화학연구원 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의약학적으로 허용가능한 염, 이의 제조방법 및 이를유효성분으로 함유하는 이상세포 성장 질환의 예방 및치료용 약학적 조성물
JP5774982B2 (ja) 2008-05-19 2015-09-09 サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． イミダゾ［１，２−ａ］ピリジン化合物
KR20110019385A (ko) 2008-05-29 2011-02-25 서트리스 파마슈티컬즈, 인코포레이티드 시르투인 조절제로서의 이미다조피리딘 및 관련 유사체
EP2323665B1 (fr) 2008-07-24 2013-06-19 Bristol-Myers Squibb Company Composés hétérocycliques condensés utiles en tant que modulateurs de kinases
US9643922B2 (en) 2008-08-18 2017-05-09 Yale University MIF modulators
US9540322B2 (en) 2008-08-18 2017-01-10 Yale University MIF modulators
JP2011231017A (ja) 2008-09-09 2011-11-17 Nissan Chem Ind Ltd 光学活性エポキシ化合物及び光学活性スルホキシド化合物の製造方法、並びに該方法に用いる配位子、錯体及び該錯体の製造方法
EP2365970B1 (fr) 2008-11-12 2018-03-21 Gilead Connecticut, Inc. Pyridazinones et leur utilisation comme inhibiteurs btk
DK2376490T3 (da) 2008-12-04 2013-04-15 Proximagen Ltd Imidazopyridinforbindelser
WO2010080474A1 (fr) 2008-12-19 2010-07-15 Bristol-Myers Squibb Company Carbazole et inhibiteurs de la carboline kinase
ES2539620T3 (es) 2008-12-19 2015-07-02 Cephalon, Inc. Pirrolotriazina como inhibidor de ALK y de JAK2
SG171815A1 (en) 2008-12-19 2011-07-28 Bristol Myers Squibb Co Carbazole carboxamide compounds useful as kinase inhibitors
JP5624275B2 (ja) 2008-12-22 2014-11-12 ユー・ディー・シー アイルランド リミテッド 有機電界発光素子
RU2505540C2 (ru) 2008-12-23 2014-01-27 Эббви Инк. Антивирусные соединения
WO2010074284A1 (fr) 2008-12-26 2010-07-01 味の素株式会社 Composé de pyrazolopyrimidine
JP2010202530A (ja) 2009-02-27 2010-09-16 Tokyo Institute Of Technology 含ヘテロ芳香族化合物および光学材料
KR20100101054A (ko) 2009-03-07 2010-09-16 주식회사 메디젠텍 세포핵에서 세포질로의 ｇｓｋ３의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 ｇｓｋ３ 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물
SG10201401169QA (en) 2009-04-02 2014-05-29 Merck Serono Sa Dihydroorotate dehydrogenase inhibitors
CA2756759C (fr) 2009-04-16 2017-11-07 Joaquin Pastor Fernandez Imidazopyrazines pour une utilisation en tant qu'inhibiteurs de kinase
US8338441B2 (en) 2009-05-15 2012-12-25 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication
US8993604B2 (en) 2009-06-30 2015-03-31 Siga Technologies, Inc. Treatment and prevention of dengue virus infections
EP2448410A4 (fr) 2009-06-30 2013-12-18 Siga Technologies Inc Traitement et prévention d'infections par le virus de la dengue
TWI625121B (zh) 2009-07-13 2018-06-01 基利科學股份有限公司 調節細胞凋亡信號之激酶的抑制劑
JP2011057661A (ja) 2009-08-14 2011-03-24 Bayer Cropscience Ag 殺虫性カルボキサミド類
UA108363C2 (uk) 2009-10-08 2015-04-27 Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування
WO2011047129A1 (fr) 2009-10-15 2011-04-21 Southern Research Institute Traitement de maladies neurodégénératives, cause d'amélioration de la mémoire et analyse pour évaluer des composés associés
NZ599291A (en) 2009-10-16 2014-06-27 Melinta Therapeutics Inc Antimicrobial compounds and methods of making and using the same
WO2011050245A1 (fr) 2009-10-23 2011-04-28 Yangbo Feng Hétéroaryles bicycliques formant inhibiteurs de la kinase
WO2011078221A1 (fr) 2009-12-24 2011-06-30 味の素株式会社 Composés d'imidazopyridazine
WO2011082400A2 (fr) 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci
US20130085133A1 (en) 2010-02-08 2013-04-04 Sourthern Research Institute Office of Commercialization and Intellectual Prop. Anti-viral treatment and assay to screenfor anti-viral agent
AR080433A1 (es) 2010-03-02 2012-04-11 Merck Sharp & Dohme Derivados de benzofurancarboxamidas utiles para tratar o prevenir infecciones por vhc y composiciones farmaceuticas que los contienen.
CN102869256B (zh) 2010-03-04 2016-06-22 默沙东公司 儿茶酚o-甲基转移酶抑制剂及其在治疗精神障碍中的用途
RU2576662C2 (ru) 2010-03-18 2016-03-10 Энститю Пастер Корея Противоинфекционные соединения
US8410117B2 (en) 2010-03-26 2013-04-02 Hoffmann-La Roche Inc. Imidazopyrimidine derivatives
EP2582668B1 (fr) 2010-06-16 2016-01-13 Bristol-Myers Squibb Company Composes carboline carboxamide utiles en tant qu'inhibiteurs de kinase
CN102295642B (zh) 2010-06-25 2016-04-06 中国人民解放军军事医学科学院毒物药物研究所 2-芳基咪唑并[1,2-a]吡啶-3-乙酰胺衍生物、其制备方法及用途
EP2402345A1 (fr) 2010-06-29 2012-01-04 Basf Se Composés pyrazoliques bicycliques condenses
CN101891895B (zh) 2010-07-28 2011-11-30 南京航空航天大学 基于桥联双水杨醛结构的苯并噻唑类金属配位聚合物及其制法及应用
WO2012016133A2 (fr) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Inhibiteurs de la ros1 kinase pour le traitement de glioblastome et d'autres cancers déficients en p53
US8633200B2 (en) 2010-09-08 2014-01-21 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
CN101993415B (zh) 2010-09-15 2013-08-14 北京韩美药品有限公司 作为Hedgehog通路抑制剂的化合物以及包含该化合物的药物组合物及其应用
CN103889428A (zh) 2010-10-04 2014-06-25 肝炎与病毒研究所 乙型肝炎病毒抗原分泌的新型抑制剂
WO2012052745A1 (fr) 2010-10-21 2012-04-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Combinaisons d'inhibiteurs de pi3k avec un second agent antitumoral
EP2444084A1 (fr) 2010-10-21 2012-04-25 Centro Nacional de Investigaciones Oncológicas (CNIO) Utilisation d'inhibiteurs de PI3K pour le traitement de l'obésité
JP6261340B2 (ja) 2010-11-18 2018-01-17 リガンド ファーマシューティカルズ インコーポレイテッド 造血成長因子模倣体の使用
US20130253011A1 (en) 2010-12-17 2013-09-26 Syngenta Participations Ag Insecticidal compounds
TWI617559B (zh) 2010-12-22 2018-03-11 江蘇恆瑞醫藥股份有限公司 ２－芳基咪唑并［１，２－ｂ］嗒．２－苯基咪唑并［１，２－ａ］吡啶，和２－苯基咪唑并［１，２－ａ］吡衍生物
MX347391B (es) 2011-01-04 2017-04-25 Novartis Ag Compuestos de indol o análogos de los mismos útiles para el tratamiento de degeneración macular relacionada con la edad (amd).
CA2825098C (fr) 2011-01-27 2020-03-10 Universite De Montreal Pyrazolopyridine et derives de pyrazolopyrimidine en tant que modulateurs du recepteur de la melanocortine-4
US8921368B2 (en) 2011-03-17 2014-12-30 Bristol-Myers Squibb Company Pyrrolopyridazine JAK3 inhibitors and their use for the treatment of inflammatory and autoimmune diseases
WO2012129562A2 (fr) 2011-03-24 2012-09-27 The Scripps Research Institute Composés et procédés pour l'induction de la chondrogenèse
MX2013011947A (es) 2011-04-13 2014-01-16 Merck Sharp & Dohme Iminotiazinas 5-sustituidas y sus monoxidos y dioxidos como inhibidores de la enzima que encinde la proteina precursora amiloide en el sitio beta, composiciones y su uso.
CN102796103A (zh) 2011-05-23 2012-11-28 南京英派药业有限公司 6-（芳基甲酰）咪唑并[1,2-a]嘧啶和6-（芳基甲酰）[1,2,4]三唑并[4,3-a]嘧啶作为Hedgehog抑制剂及其应用
WO2012166951A1 (fr) 2011-05-31 2012-12-06 Receptos, Inc. Nouveaux stabilisants et modulateurs du récepteur de glp-1
GB201109763D0 (en) 2011-06-10 2011-07-27 Ucl Business Plc Compounds
WO2012175991A1 (fr) 2011-06-24 2012-12-27 Pharminox Limited Composés pentacycliques fusionnés anti-prolifératifs
JP6145451B2 (ja) 2011-07-08 2017-06-14 ノバルティス アーゲー 新規なピロロピリミジン誘導体
EP2548877A1 (fr) 2011-07-19 2013-01-23 MSD Oss B.V. Dérivés de 4-(pyridine condensée à 5 chaînons)benzamide comme inhibiteurs de BTK
WO2013033901A1 (fr) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Dérivés benzofuranes substitués par un hétérocycle et leurs procédés d'utilisation pour le traitement de maladies virales
WO2013040528A1 (fr) 2011-09-16 2013-03-21 Microbiotix, Inc. Composés antimicrobiens
WO2013043521A1 (fr) * 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Composés pyrazolopyridyle à utiliser en tant qu'inhibiteurs de l'aldostérone synthase
JP6040677B2 (ja) 2011-09-29 2016-12-07 東洋インキＳｃホールディングス株式会社 太陽電池封止材用樹脂組成物
CN103987710A (zh) 2011-10-13 2014-08-13 诺华股份有限公司 新的*嗪衍生物及它们在治疗疾病中的应用
WO2013059594A1 (fr) 2011-10-20 2013-04-25 Sirtris Pharmaceuticals, Inc. Aza-hétérocycles bicycliques substitués et analogues en tant que modulateurs des sirtuines
US20150126530A1 (en) 2011-10-21 2015-05-07 Torrent Pharmaceuticals Limited Novel Substituted Imidazopyrimidines as Gpbar1 Receptor Modulators
WO2013120040A1 (fr) 2012-02-10 2013-08-15 Children's Medical Center Corporation Inhibition d'une voie ciblée pour améliorer la structure, le fonctionnement et l'activité musculaires dans la dystrophie musculaire
US9034882B2 (en) 2012-03-05 2015-05-19 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
IN2014MN01897A (fr) 2012-03-09 2015-07-10 Carna Biosciences Inc
TWI480271B (zh) 2012-04-20 2015-04-11 Gilead Sciences Inc 醫療性化合物
WO2013157021A1 (fr) 2012-04-20 2013-10-24 Advinus Therapeutics Limited Composés bicycliques, compositions et applications médicinales de ceux-ci
WO2013163404A1 (fr) 2012-04-27 2013-10-31 The Uab Research Foundation Traitement d'infections virales avec arn viraux traduits par un mécanisme non médié par l'ires
WO2013191113A1 (fr) 2012-06-18 2013-12-27 住友化学株式会社 Composé hétérocyclique fusionné
WO2014007228A1 (fr) 2012-07-03 2014-01-09 小野薬品工業株式会社 Composé ayant une activité agoniste sur un récepteur de la somatostatine, et leur utilisation à des fins médicales
WO2014009295A1 (fr) 2012-07-13 2014-01-16 Ucb Pharma S.A. Dérivés d'imidazopyridine utilisables en tant que modulateurs de l'activité tnf
GB201212513D0 (en) 2012-07-13 2012-08-29 Ucb Pharma Sa Therapeutic agents
JP2015178457A (ja) 2012-07-25 2015-10-08 杏林製薬株式会社 ピラゾロピリジン誘導体、またはその薬理学的に許容される塩
EP2892899B1 (fr) 2012-09-06 2018-03-21 Bristol-Myers Squibb Company Inhibiteurs de jak3 de type imidazopyridazine et leur utilisation pour le traitement de maladies inflammatoires et auto-immunes
DK2900657T3 (da) 2012-09-26 2020-05-04 Hoffmann La Roche Cykliske etherpyrazol-4-yl-heterocyclyl-carboxamidforbindelser og fremgangsmåder til anvendelse
WO2014061693A1 (fr) 2012-10-17 2014-04-24 塩野義製薬株式会社 Nouveau dérivé carbocyclique non aromatique ou hétérocyclique non aromatique
US9163027B2 (en) 2012-11-21 2015-10-20 Stategics, Inc. Substituted triazolo-pyrimidine compounds for modulating cell proliferation differentiation and survival
JP6037804B2 (ja) 2012-12-03 2016-12-07 富士フイルム株式会社 ガス分離膜
EA035929B1 (ru) 2013-01-15 2020-09-02 Инсайт Холдингс Корпорейшн ТИАЗОЛКАРБОКСАМИДЫ И ПИРИДИНКАРБОКСАМИДЫ, ИСПОЛЬЗУЕМЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ Pim-КИНАЗЫ
RU2015132181A (ru) 2013-01-22 2017-03-02 Ф. Хоффманн-Ля Рош Аг Фтор-[1,3]-оксазины в качестве ингибиторов васе1
CN103933036B (zh) 2013-01-23 2017-10-13 中国人民解放军军事医学科学院毒物药物研究所 2‑芳基咪唑并[1,2‑α]吡啶‑3‑乙酰胺衍生物在制备防治PTSD的药物中的用途
US9657082B2 (en) 2013-01-31 2017-05-23 Thomas Jefferson University PD-L1 and PD-L2-based fusion proteins and uses thereof
AU2014221799B2 (en) 2013-02-27 2017-09-28 Mochida Pharmaceutical Co., Ltd. Novel pyrazole derivative
JP6374889B2 (ja) 2013-03-08 2018-08-15 アムジエン・インコーポレーテツド β−セクレターゼ阻害剤としての過フッ素化シクロプロピル縮合１，３−オキサジン−２−アミン化合物、及び使用方法
CN104045552B (zh) 2013-03-13 2019-06-11 江苏先声药业有限公司 作为神经保护剂的药用化合物
US20160050895A1 (en) 2013-03-13 2016-02-25 Australian Nuclear Science And Technology Organization Transgenic non-human organisms with non-functional tspo genes
ES2705247T3 (es) 2013-03-14 2019-03-22 Univ Columbia 4-fenilpiperidinas, su preparación y uso
WO2014159959A1 (fr) 2013-03-14 2014-10-02 Bristol-Myers Squibb Company Inhibiteurs de la réplication du virus de l'immunodéficience humaine
CA2906086A1 (fr) 2013-03-14 2014-09-25 Celtaxsys, Inc. Inhibiteurs de la leucotriene a4 hydrolase
EA201591610A1 (ru) 2013-03-14 2015-12-30 Курадев Фарма Прайвит Лтд. Ингибиторы кинуренинового пути
US9308236B2 (en) 2013-03-15 2016-04-12 Bristol-Myers Squibb Company Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
WO2014181287A1 (fr) 2013-05-09 2014-11-13 Piramal Enterprises Limited Composés hétérocyclyliques et leurs utilisations
CA2916298C (fr) 2013-06-26 2021-10-12 Abbvie Inc. Carboxamides primaires servant d'inhibiteurs de la btk
BR112016000059B1 (pt) 2013-07-02 2020-12-29 Syngenta Participations Ag compostos heterociclos bi ou tricíclicos, composição compreendendo os referidos compostos, método para combater e controlar pragas, método para a proteção de material de propagação vegetal do ataque por pragas e material de propagação vegetal revestido com a referida composição
CN105408325B (zh) 2013-07-17 2019-10-22 大塚制药株式会社 氰基三唑化合物
KR20160034379A (ko) 2013-07-25 2016-03-29 다나-파버 캔서 인스티튜트 인크. 전사 인자의 억제제 및 그의 용도
EP2835375A1 (fr) 2013-08-09 2015-02-11 Fundació Institut Català d'Investigació Química Composés salphen bis et composites de matériau carboné les comprenant
KR101715090B1 (ko) 2013-08-28 2017-03-13 한국화학연구원 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 인플루엔자 바이러스 감염으로 인한 질환의 예방 또는 치료용 약학적 조성물
EP3041822B1 (fr) 2013-09-04 2017-08-09 Bristol-Myers Squibb Company Composés utiles comme immunomodulateurs
CN105849092A (zh) 2013-09-06 2016-08-10 奥瑞基尼探索技术有限公司 作为免疫调节剂的1，3，4-*二唑和1，3，4-噻二唑衍生物
LT3041827T (lt) 2013-09-06 2018-07-25 Aurigene Discovery Technologies Limited 1,2,4-oksadiazolo dariniai, kaip imunomoduliatoriai
WO2015036927A1 (fr) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Dérivés peptidomimétiques d'immunomodulation
JP6336870B2 (ja) 2013-09-30 2018-06-06 日本ポリプロ株式会社 ビフェノール化合物及びそれを用いるオレフィン重合用触媒並びにオレフィン重合体の製造方法
FR3012140B1 (fr) 2013-10-18 2016-08-26 Arkema France Unite et procede pour la purification de methacrylate de methyle brut
GB201321733D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321746D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321736D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
WO2015095337A2 (fr) 2013-12-18 2015-06-25 The Rockefeller University Dérivés pyrazolo [1,5-a]pyrimidine carboxamide pour le traitement de troubles cognitifs
EP3089972B1 (fr) 2014-01-03 2018-05-16 Bayer Animal Health GmbH Nouveaux pyrazol-hétéroarylamides comme moyen de lutte contre les parasites
CA2938152A1 (fr) 2014-02-10 2015-08-13 Merck Sharp & Dohme Corp. Anticorps qui se lient a la proteine tau humaine et dosage pour quantifier la proteine tau humaine au moyen des anticorps
ES2771950T3 (es) 2014-02-25 2020-07-07 Achillion Pharmaceuticals Inc Compuestos de arilo, heteroarilo y heterocíclicos para el tratamiento de trastornos mediados por el complemento
JP6490464B2 (ja) 2014-03-26 2019-03-27 三井化学株式会社 遷移金属化合物、オレフィン重合用触媒およびオレフィン系重合体の製造方法
GEP20217247B (en) 2014-04-04 2021-04-26 Iomet Pharma Ltd Gb Indole derivatives for use in medicine
US9850225B2 (en) * 2014-04-14 2017-12-26 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015197028A1 (fr) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Composés en tant qu'inhibiteurs du virus de l'hépatite c (vhc) et leurs utilisations en médecine
CN104211726B (zh) 2014-08-11 2017-06-16 中南民族大学 非茂类三齿双核钛配合物、制备方法及用途
US20170305922A1 (en) 2014-09-17 2017-10-26 Epizyme, Inc. Carm1 inhibitors and uses thereof
EP3204382B1 (fr) 2014-10-06 2021-12-01 Merck Patent GmbH Composés hétéroaryle servant d'inhibiteurs de la btk, et leurs utilisations
US10017520B2 (en) 2014-12-10 2018-07-10 Massachusetts Institute Of Technology Myc modulators and uses thereof
JP6853619B2 (ja) 2015-01-16 2021-03-31 大塚製薬株式会社 シアノトリアゾール化合物の医薬用途
WO2016116525A1 (fr) 2015-01-20 2016-07-28 Cynora Gmbh Molécules organiques, notamment pour une utilisation dans des composants opto-électroniques
WO2016118404A1 (fr) 2015-01-20 2016-07-28 Merck Sharp & Dohme Corp. Dioxydes d'iminothiadiazine portant un substituant lié à une amine, utilisés en tant qu'inhibiteurs de bace, compositions les contenant et leur utilisation
WO2016156282A1 (fr) 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Nouveaux composés de triazole pour contrôler des champignons nocifs phytopathogènes
WO2017035405A1 (fr) 2015-08-26 2017-03-02 Achillion Pharmaceuticals, Inc. Composés amino pour le traitement de troubles immunitaires et inflammatoires
US10745382B2 (en) 2015-10-15 2020-08-18 Bristol-Myers Squibb Company Compounds useful as immunomodulators
TW201718581A (zh) 2015-10-19 2017-06-01 英塞特公司 作為免疫調節劑之雜環化合物
WO2017070320A1 (fr) 2015-10-21 2017-04-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Inhibiteurs allostériques de phényl indole de l'atpase p97
KR101717601B1 (ko) 2015-11-10 2017-03-20 한국화학연구원 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 인플루엔자 바이러스 감염으로 인한 질환의 예방 또는 치료용 약학적 조성물
WO2017087777A1 (fr) 2015-11-19 2017-05-26 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
TW201726623A (zh) 2015-12-17 2017-08-01 英塞特公司 作為免疫調節劑之雜環化合物
US20170174679A1 (en) 2015-12-22 2017-06-22 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017107052A1 (fr) 2015-12-22 2017-06-29 Merck Sharp & Dohme Corp. Activateurs solubles de guanylate cyclase
AU2016378482A1 (en) 2015-12-22 2018-07-12 Synthon B.V. Pharmaceutical composition comprising amorphous lenalidomide and an antioxidant
CN108463109B (zh) 2015-12-22 2022-04-29 先正达参股股份有限公司 杀有害生物活性吡唑衍生物
SG10202111399YA (en) 2015-12-22 2021-11-29 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers
KR101653560B1 (ko) 2016-02-02 2016-09-12 한국화학연구원 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 인플루엔자 바이러스 감염으로 인한 질환의 예방 또는 치료용 약학적 조성물
EP3452476B1 (fr) 2016-05-06 2021-12-15 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
WO2017205464A1 (fr) 2016-05-26 2017-11-30 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
SMT202200392T1 (it) 2016-06-20 2022-11-18 Incyte Corp Composti eterociclici come immunomodulatori
PT3471755T (pt) 2016-06-20 2020-05-22 Elanco Us Inc Interferão suíno peguilado e métodos de utilização do mesmo
JP7042812B2 (ja) 2016-06-20 2022-03-28 ノバルティス アーゲー トリアゾロピリミジン化合物の結晶形態
EP3471727B1 (fr) 2016-06-21 2020-12-09 X4 Pharmaceuticals, Inc. Inhibiteurs de cxcr4 et leurs utilisations
ES2930092T3 (es) 2016-07-14 2022-12-07 Incyte Corp Compuestos heterocíclicos como inmunomoduladores
AU2017305399A1 (en) 2016-08-03 2019-01-31 Arising International, Inc. Symmetric or semi-symmetric compounds useful as immunomodulators
WO2018044783A1 (fr) 2016-08-29 2018-03-08 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
MA46102A (fr) 2016-08-30 2019-07-10 Tetraphase Pharmaceuticals Inc Composés de tétracycline et méthodes de traitement
TWI795381B (zh) 2016-12-21 2023-03-11 比利時商健生藥品公司 作為ｍａｌｔ１抑制劑之吡唑衍生物
US10858364B2 (en) 2016-12-21 2020-12-08 Acerta Pharma B.V. Imidazopyrazine inhibitors of Bruton's tyrosine kinase
US20180177784A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
ES2934230T3 (es) 2016-12-22 2023-02-20 Incyte Corp Derivados de benzooxazol como inmunomoduladores
US20180179179A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
AU2017382405B2 (en) 2016-12-22 2021-12-16 Calithera Biosciences, Inc. Compositions and methods for inhibiting arginase activity
EP3558963B1 (fr) 2016-12-22 2022-03-23 Incyte Corporation Composés hétéroaromatiques bicycliques utilisés en tant qu'immunomodulateurs
EP3558989B1 (fr) 2016-12-22 2021-04-14 Incyte Corporation Dérivés de triazolo[1,5-a]pyridine en tant qu'immunomodulateurs
CN110267953B (zh) 2016-12-22 2022-12-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
JOP20180040A1 (ar) 2017-04-20 2019-01-30 Gilead Sciences Inc مثبطات pd-1/pd-l1
KR102647257B1 (ko) 2017-07-28 2024-03-13 케모센트릭스, 인크. 면역조절제 화합물
MA49859A (fr) 2017-08-08 2021-04-07 Chemocentryx Inc Immunomodulateurs macrocycliques
US11787766B2 (en) 2017-08-18 2023-10-17 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Compound having PD-L1 inhibitory activity, preparation method therefor and use thereof
PL3774791T3 (pl) 2018-03-30 2023-06-05 Incyte Corporation Związki heterocykliczne jako immunomodulatory
EP3774750A4 (fr) 2018-04-03 2021-12-29 Betta Pharmaceuticals Co., Ltd Immunomodulateurs, compositions et procédés associés
CN112041311B (zh) 2018-04-19 2023-10-03 吉利德科学公司 Pd-1/pd-l1抑制剂
TWI821288B (zh) 2018-05-11 2023-11-11 美商英塞特公司 作為免疫調節劑之雜環化合物
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
JP2022513592A (ja) 2018-11-02 2022-02-09 シャンハイ マキシノベル ファーマシューティカルズ カンパニー リミテッド ビフェニル系化合物、その中間体、製造方法、医薬組成物及び使用
AU2020214404B2 (en) 2019-01-31 2025-04-24 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods thereof
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
JP7559059B2 (ja) 2019-09-30 2024-10-01 インサイト・コーポレイション 免疫調節剤としてのピリド［３，２－ｄ］ピリミジン化合物
CR20220237A (es) 2019-11-11 2022-08-05 Incyte Corp Sales y formas cristalinas de un inhibidor de pd-1/pd-l1

Also Published As

Publication number Publication date
US20210347771A1 (en) 2021-11-11
TW201718581A (zh) 2017-06-01
EP3365340A1 (fr) 2018-08-29
US20170107216A1 (en) 2017-04-20
WO2017070089A1 (fr) 2017-04-27
US20190144439A1 (en) 2019-05-16
US11407749B2 (en) 2022-08-09
MA52119A (fr) 2018-08-29
HK1258272A1 (en) 2019-11-08
ES2928164T3 (es) 2022-11-15

Similar Documents

Publication Publication Date Title
US11407749B2 (en) Heterocyclic compounds as immunomodulators
US11866435B2 (en) Heterocyclic compounds as immunomodulators
AU2021250978B2 (en) Heterocyclic compounds as immunomodulators
EP3558989B1 (fr) Dérivés de triazolo[1,5-a]pyridine en tant qu'immunomodulateurs
EP3452476B1 (fr) Composés hétérocycliques utilisés comme immunomodulateurs
EP3558973B1 (fr) Dérivés pyridine utilisés en tant qu'immunomodulateurs
EP3377488B1 (fr) Composés hétérocycliques utilisés comme immunomodulateurs
HK40053556A (en) Heterocyclic compounds as immunomodulators
HK1258272B (en) Heterocyclic compounds as immunomodulators
HK40006033B (en) Heterocyclic compounds as immunomodulators
HK40006033A (en) Heterocyclic compounds as immunomodulators
HK40014225A (en) Triazolo[1,5-a]pyridine derivatives as immunomodulators
HK40014225B (en) Triazolo[1,5-a]pyridine derivatives as immunomodulators
HK40004473B (en) Heterocyclic compounds as immunomodulators
HK40004473A (en) Heterocyclic compounds as immunomodulators
HK40014224A (en) Pyridine derivatives as immunomodulators
HK40014224B (en) Pyridine derivatives as immunomodulators
HK1260843A1 (en) Heterocyclic compounds as immunomodulators
HK1260843B (en) Heterocyclic compounds as immunomodulators
NZ788114A (en) Heterocyclic compounds as immunomodulators
HK1259752A1 (en) Heterocyclic compounds as immunomodulators
HK1259752B (en) Heterocyclic compounds as immunomodulators

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20180518

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1258272

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20201203

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20211004

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTC Intention to grant announced (deleted)
INTG Intention to grant announced

Effective date: 20220307

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1510467

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220815

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602016074172

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2928164

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20221115

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20220810

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221212

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221110

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1510467

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221210

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MD

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602016074172

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20221031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221018

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230526

26N No opposition filed

Effective date: 20230511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221031

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20221031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20161018

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220810

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20241001

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20241001

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20241001

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20241001

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20241010

Year of fee payment: 9

Ref country code: ES

Payment date: 20241107

Year of fee payment: 9

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MA

Free format text: FAILURE TO ELECT DOMICILE IN THE NATIONAL COUNTRY

Effective date: 20221111